key: cord-1004774-8iptyxho
authors: Kok, Lianne; Masopust, David; Schumacher, Ton N.
title: The precursors of CD8(+) tissue resident memory T cells: from lymphoid organs to infected tissues
date: 2021-09-03
journal: Nat Rev Immunol
DOI: 10.1038/s41577-021-00590-3
sha: a5e447098cce3d4b0190fb657363b2a20610e7ec
doc_id: 1004774
cord_uid: 8iptyxho

CD8(+) tissue resident memory T cells (T(RM) cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to T(RM) cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature T(RM) cells, and it was therefore long assumed that T(RM) cell formation adheres to a ‘local divergence’ model, in which T(RM) cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a ‘systemic divergence’ model, in which circulating T cells already become preconditioned to preferentially give rise to the T(RM) cell lineage, resulting in the generation of a pool of T(RM) cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating T(RM) cell progenitors, discuss current insights into their formation and highlight open questions in the field.

A fundamental aspect of CD8 + T cells is their ability to adapt to the type of pathogens encountered. First, through the process of clonal expansion upon antigen recognition, the T cell pool becomes biased to recog nize pathogens that it has previously been exposed to 1 . Second, remodelling of the epigenetic landscape allows memory cells that are formed in this process to more rapidly exert effector functions 2 . Third, the distribution of the CD8 + T cell memory compartment over diffe r ent body sites maximizes the chance of early pathogen recognition upon renewed infection 3 . In line with the concept that the CD8 + memory T cell pool can provide rapid effector functions and has the capacity for renewed clonal expansion, this cell pool is highly diverse at the epigenetic, transcriptional and protein expression levels. Specifically, within the circulation (that is, blood, lymph and secondary lymphoid organs) two main sub groups of CD8 + memory T cells can be distinguished, often referred to as CD8 + central memory T cells (T CM cells) and CD8 + effector memory T cells (T EM cells), which collec tively form the pool of CD8 + circulating memory T cells (here jointly referred to as T CIRCM cells). T CM cells can be distinguished by high level expression of the lymphoid homing markers CD62L and CCR7. They are considered to be multipotent and at least a subset of this cell pool display a heightened expansion potential upon antigen re encounter 4 . By contrast, T EM cells possess limited expansion potential and lack the ability to enter lymph nodes from the blood, but are marked by expression of cytotoxicity associated genes and can exert rapid effector functions upon renewed TCR signalling 5 . T EM cells were long believed to be superior in penetrating and survey ing peripheral tissues; however, this idea has come under scrutiny as recent work has suggested that T EM cells and T EM cell like cells are mostly excluded from human and mouse non lymphoid tissues (NLTs) [6] [7] [8] [9] .

In addition to the systemic CD8 + memory T cell pool, a pool of CD8 + tissue resident memory T cells (T RM cells) that permanently reside within NLTs can be distin guished. Through a process of continuous migration and surveillance that is confined to distinct anatomic compartments, such as the stroma or the parenchyma of organs, T RM cells patrol tissues to scan for foreign invaders 10, 11 . Following antigen encounter, T RM cells rapi dly induce a local state of alarm, resulting in the recruit ment of other immune cells and the local production of antimicrobial and antiviral proteins by epithelial cells 12, 13 . In line with this 'pathogen alert' function, T RM cells not only produce cytotoxicity associated molecules, such as granzyme B and perforin, but also cytokines such as IFNγ and TNF that can influence the behaviour of neighbouring cells [14] [15] [16] [17] [18] [19] . Furthermore, the existence of T RM cells that express minimal levels of cytolytic mole cules, and may therefore mostly rely on this 'pathogen alert' function, has been reported in various human tissues [20] [21] [22] [23] . Whereas T RM cells share transcriptional fea tures with both T CM cells and T EM cells, they are unique in their expression of a tissue residency promoting CD8 + central memory T cells (CD8 + T CM cells). CD8 + memory T cells with a high degree of proliferative potential upon reactivation, commonly identified by the expression of lymphoid homing marker CD62L, and that can be abundantly found in the spleen, blood and lymph nodes.

CD8 + effector memory T cells (CD8 + T EM cells). CD8 + memory T cells with a high degree of cytotoxicity upon reactivation, which are commonly identified by the lack of CD62L expression, and that can be abundantly found in the spleen and blood.

The precursors of CD8 + tissue resident memory T cells: from lymphoid organs to infected tissues Lianne Kok 1 , David Masopust 2 and Ton N. Schumacher 1 ✉ Abstract | CD8 + tissue resident memory T cells (T RM cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to T RM cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature T RM cells, and it was therefore long assumed that T RM cell formation adheres to a 'local divergence' model, in which T RM cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a 'systemic divergence' model, in which circulating T cells already become preconditioned to preferentially give rise to the T RM cell lineage, resulting in the generation of a pool of T RM cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating T RM cell progenitors, discuss current insights into their formation and highlight open questions in the field. transcriptional signature, which marks T RM cells in a wide range of tissues. Besides this core tissue residency signa ture, T RM cells also display transcriptional features that are specific to individual tissues and allow their survival and long term retention at those different sites 24, 25 .

The residency signature that marks T RM cells in multi ple tissues is characterized both by a reduced expression of proteins that promote tissue egress and a heightened expression of proteins that promote tissue retention. For instance, T RM cells show reduced expression of the cell surface molecules S1PR1 and CCR7 that promote T cells to leave NLTs, an observation that is explained by a lowered expression of the transcription factor KLF2, which drives S1PR1 and CCR7 transcription 26 . On the other hand, T RM cells express CD69 and, in the case of T RM cells localized within epithelial tissues, the E cadherin binding αE integrin (CD103, encoded by Itgae), which both promote tissue retention (for a comprehensive review of the molecular pathways that control tissue retention, please see rEf. 27 ). The expres sion of CD69 and CD103 should be considered imper fect markers to infer tissue residency, as absence of their expression does not rule out long term tissue retention and presence of expression does not exclude the poten tial to leave NLTs [28] [29] [30] [31] [32] . Nevertheless, much of our current understanding of T RM cells is based on analyses of CD69 + CD103 + T RM cells in epithelial tissues.

In line with their role as local sentinels, T RM cells have been shown to both prevent and exacerbate patho logies. For instance, T RM cells are not only superior to T CIRCM cells in conferring protection to recurring local pathogens 33, 34 but these cells can also provide protec tion against the development of skin malignancies [35] [36] [37] . Moreover, tumour infiltrating lymphocytes that strongly resemble conventional T RM cells have been associated with improved disease prognosis 38, 39 . At the same time, T RM cells may drive immunotherapy induced colitis 40 , the skin autoimmune disorders vitiligo 41 and psoriasis 42, 43 and also other autoimmune and allergic diseases 44 , and may play a central role in allograft rejection 45 . The involvement of T RM cells in a range of human diseases makes the design of therapeutic strate gies that can modulate either their production or their activity an attractive goal, and to realize this goal, it is critical to understand how the formation of this cell pool is regulated 46 . In this Review, we discuss the pro cesses that drive the formation of the CD103 + epithelial T RM cell lineage, with a strong focus on signalling events that occur within the lymphoid compartment.

T Rm cell precursors within NLTs At an early stage of an antigen specific CD8 + T cell response, infected tissues are seeded by CD8 + effectorstage T cells (T EFF cells); that is, activated T cells that can be observed around the peak of the expansion phase, regardless of their phenotype and function 47 . T EFF cells forming the first wave of T cells that can be detected at inflamed sites already show transcriptional differences relative to circulating T cells that are specific for the same antigen 14, 48 . Differentially expressed genes are asso ciated with a wide range of cellular functions, includ ing cell adhesion, cytokine and chemokine signalling, co stimulation and co inhibition, and transcriptional regulation 14, 48 . Interestingly, early T EFF cells present at the tissue site display increased expression of core T RM cell genes, and at the peak of the T cell response the T cell population present at the tissue site already expresses more than 90% of the gene signature that differentiates T RM cells from T CIRCM cells 49 . This illus trates that the initiation of a T RM cell differentiation pro cess already occurs during early stages of the immune response.

Although the T EFF cells at tissue sites show a rapid transcriptional and phenotypic divergence from their circulating counterparts, these T EFF cells nevertheless do display the same diversity in cell states that has previously been described for circulatory T EFF cells. Specifically, within the circulating T EFF cell compart ment, two cell states are commonly distinguished: the relatively short lived terminal effector cells that express high levels of KLRG1, T BET and BLIMP1 and show high cytotoxic potential; and the memory precursor cells that give rise to stable circulating memory T cell popula tions and are generally defined by an elevated expression of IL7Rα, ID3 and TCF1 (rEf. 50 ). A similar dichotomy in phenotype and fate has been documented for the pool of T EFF cells within NLTs [51] [52] [53] . Furthermore, T cells in NLTs that resemble circulating terminal effector T cells fail to express the T RM associated markers CD103 and CD69, and gradually perish over time 51, 52 . On the contrary, T cells within NLTs that resemble memory precursor cells express CD103 and CD69, indicative of their poten tial to persist long term within the NLTs 51, 52 . Interestingly, at very early stages of the immune response, before the appearance of cells with the terminally differentiated (KLRG1 + IL7Rα − ) phenotype, two transcriptionally disparate subgroups of T EFF cells that differ in their dif ferentiation potential can already be distinguished in the epithelium of the small intestine. Specifically, early effec tor T cells that are marked by high expression of IL2Rα and EZH2, an epigenetic regulator known to modulate early effector T cell fate decisions 54, 55 , are prone to give rise to KLRG1 + terminal effector T cell like cells, in con trast to their EZH2 low IL2Rα LO low counterparts that are superior in the generation of CD103 + CD69 + T RM cells 48 .

Numerous signals that promote the differentiation of T RM cells within the tissue micro environment have been described, and these signals presumably contri bute significantly to the emergence of cells with T RM cell like properties at the tissue site early during the immune response. For example, the presence of antigen 56-60 , IL7 (rEf. 61 ), IL15 (rEfs 41, 52, [61] [62] [63] and TGFβ 64,65 within the non lymphoid micro environment promote T RM cell differentiation in tissues such as the skin and lung. In particular, TGFβ is considered a central mediator of epithelial T RM cell differentiation as it can modulate the expression of many molecules that specifically mark T RM cells 26, 62, 66, 67 . In line with this, T cells that are insen sitive to TGFβ signalling lack the capacity to develop into CD103 + CD69 + T RM cell precursors and T RM cells in many epithelial tissues 51, 57, 66, 68 . Other T cell extrinsic fac tors that can influence T RM cell formation are TNF and IL33 (rEfs 26, 66, 69 ), which can induce CD69 and CD103 expression and suppress KLF2 expression, and IL21, CD8 + circulating memory T cells (CD8 + T CIrCM cells). A collective term for all of the CD8 + memory T cells that can circulate through the body and that are predominantly found in the blood, spleen and lymph nodes; the T CIrCM cell population encompasses both the CD8 + central memory T cell (T CM cell) and the CD8 + effector memory T cell (T EM cell) lineages.

CD8 + tissue resident memory T cells (CD8 + T rM cells). CD8 + memory T cells that, under steady-state conditions, are consistently excluded from the circulation and reside in tissues; T rM cells in mucosal tissue, such as the lung, gut and skin, are typically identified as CD103 + CD69 + .

CD8 + effector-stage T cells (CD8 + T Eff cells). All activated CD8 + T cells present around the peak of the expansion phase elicited by infection or vaccination, regardless of phenotype or function.

www.nature.com/nri 0123456789();: which has recently been identified to boost the forma tion of CD103 + brain T RM cells 70 . However, a critical issue that has not been fully settled is whether these various signals primarily modulate T RM cell fate at the inflamed tissue site or may also play a role in lineage instruction in the lymphoid compartment prior to tissue entry.

It is important to note that the signals driving the formation of T RM cells differ between epithelial tissue types. For instance, abrogation of T cell intrinsic TGFβ signalling results in impaired production of T RM cells in the lung, whereas the formation of T RM cells in the nasal cavity is unaffected 71 . Similarly, IL15 signalling is required for T RM cell formation in some, but not all, tissues 72 . The idea that different routes to tissue resi dency exist is also supported by the observation that the transcription factor HOBIT promotes T RM cell develop ment in the skin and small intestine, but is not required for lung T RM cell formation 73, 74 . Collectively, these results strengthen the idea that the processes that yield T RM cells show a level of redundancy, and that environmental conditions can change the requirements for T cells to develop into T RM cells.

Based on the studies discussed above, it is apparent that the potential for T RM cell differentiation is already present in part of the T EFF cell population that is located within NLTs early during infection. However, these findings do not address whether this potential is induced only after tissue entry or is already present before that stage. An analysis of T RM cell forming potential within the pool of activated circulating T cells has shown that cells with a memory precursor phenotype possess a superior potential to yield T RM cells, but this cell pool is also well equipped to yield T CIRCM cells 49, 52, 75 . The hypothesis that the circulating memory precursor cell pool can sprout both T RM cells and T CIRCM cells is compatible with two models for T RM cell generation. In the 'local divergence' model, the circulating memory precursor pool is pro posed to consist of cells that are equal in their potential to contribute to both the T RM cell pool and the T CIRCM cell pool. Only upon stochastic tissue entry and subsequent encounter of local micro environmental factors, such as TGFβ and IL15, by a selection of memory precursor cells would these cells commit to the T RM cell lineage and adopt tissue residency (fIg. 1a) . In other words, in this model, signals within the NLTs dictate T RM cell line age commitment. In the alternative 'systemic divergence' model, events that occur prior to tissue entry, within the lymphoid tissue or in blood, already steer some memory precursor cells to their subsequent fate as T RM cells. In this model, a dichotomy in memory forming potential would already be present within the circulating memory precursor cell pool, providing part of that pool with an enhanced capacity to migrate into inflamed tissue and/or respond to inflamed tissue derived environmental factors that support T RM cell formation (fIg. 1b).

As described above, earlier work has identified numerous tissue derived factors that can support T RM cell formation, and based on these observations it was generally assumed that the tissue micro environment autonomously instructs T RM cell lineage decisions in uncommitted infiltrating memory precursor cells. However, numerous studies have subsequently identi fied factors within lymphoid tissues that are essential for the formation of the T RM cell lineage, but not the

A collective term for the thymus, bone marrow, lymph nodes and spleen; in this review, this term predominantly refers to spleen and lymph nodes.

Circulation a Tissue divergence model

Uncommitted T cell Branching of the CD8 + tissue resident memory T cell (T RM cell) lineage from the circulating T cell lineages can be explained by two models. a | The tissue divergence model postulates that memory precursors within the circulation are equal in their potential to give rise to CD8 + circulating memory T cells (T CIRCM cells) and T RM cells. Only upon reaching the tissue do cells undergo changes that skew them towards the T RM cell lineage, whereas those memory precursor T cells that remain in circulation start to differentiate into T CIRCM cell lineages. b | The systemic divergence model postulates the existence of memory precursors within the circulating T cell pool that are poised to produce the T RM cell lineage and these cells are superior in giving rise to T RM cells relative to other circulating memory precursors. Note that these models do not address whether a fraction of cells with reduced T RM cell-forming potential enter the tissue and later rejoin the circulation.

T CIRCM cell lineage. Furthermore, a combination of single cell transcriptome analysis and lineage tracing allowed identification of the existence of a circulating effector T cell population that preferentially gives rise to T RM cells and transcriptionally resembles mature T RM cells 76 . These observations argue for a 'systemic divergence' model of T RM cell formation, in which the capacity to develop into T RM cells is at least partially driven by lymphoid derived signals.

A 'systemic divergence' model of T RM cell differentiation proposes that the propensity to give rise to this lineage of memory cells is at least partially imprinted prior to tissue entry. As T RM cell precursors can already be detected in tissues at an early stage of the T cell response, any systemic imprinting of T RM cell lineage decisions should therefore also occur prior to, or within the first few days follow ing, T cell activation. Importantly, direct evidence that T cells undergo T RM cell fate conditioning/poising prior to substantial antigen driven expansion has been obtained. Specifically, two studies have shown that naive T cells, either expressing variable 77 or identical 76 TCRs, show diversity in their ability to yield T RM cells and T CIRCM cells. This observed skewing of the progeny of individual T cells to either the T RM cell or T CIRCM cell lineage can conceptually be explained by differential exposure to signals that allow T RM cell formation by early progeny, or by a gentle 'nudge' towards the production of T RM cells that is already received at the naive T cell stage, prior to TCR triggering. Notably, evidence in favour of imprint ing both during T cell priming and at the naive T cell stage has been obtained. With respect to the imprinting of T RM cell differentiation capacity during T cell priming, it is becoming increasingly evident that the specific dend ritic cell subtypes that interact with T cells within lym phoid tissues can help steer early T RM cell differentiation. For instance, priming of human T cells by CD1c + CD163 + dendritic cells may preferentially induce T RM cell fate, as suggested by the observation that in vitro activation of naive T cells by CD1c + CD163 + dendritic cells, but not other dendritic cell subsets, induces the expression of a wide range of T RM cell associated genes in human T cells, and endows cells with enhanced capacity to accumulate in human epithelial grafts in mice 78, 79 . Furthermore, data obtained in mouse models have demonstrated that only priming by BATF3 + dendritic cells, a subgroup of antigen presenting cells (APCs) that are efficient in antigen cross presentation, allowed the formation of T RM cells in skin and lung tissue 80 . Interestingly, another study comparing terminal effector T cell versus T CIRCM cell differentiation in mice demonstrated that priming mediated by BATF3 + dendritic cells favours the production of terminal effector T cells and T EM cells over T CM cells, whereas CD11b hi dend ritic cells, a subset that is poor at promoting T RM cell differentiation 80 , favoured T CM cell differentiation 81 . Although the above data indicate that BATF3 + dendritic cells can skew naive T cells towards both the T RM cell line age and the T EM cell lineage, lineage tracing data indi cate that T RM cells and T EM cells are largely derived from distinct naive T cells 76 . This apparent contradiction may potentially be explained by an unappreciated diversity in T RM /T EM cell priming abilities within the BATF3 + den dritic cell lineage, or by naive T cell intrinsic variation in T RM cell forming potential. The above data provide solid evidence that the nature of the APCs that induce T cell priming can influence their capacity to differentiate into T RM cells. In addition, evidence for such a 'sculpt ing effect' of dendritic cell encounters in the absence of antigen recognition has also been obtained. Specifically, migratory dendritic cells within lymph nodes have been reported to epigenetically reprogram naive T cells in the absence of inflammation, leading to a T RM cell-poised state that licenses naive T cells to preferentially give rise to skin T RM cells in response to local inflammation 82 .

The relative output of naive T cells towards either the T RM cell or T CIRCM cell pool after skin inflammation has been shown to be linked to the production of circulating T EFF cells with a T RM cell like transcriptional signature by the progeny of individual cells 76 . It is plausible that encounter of the above mentioned T RM cell biasing dendritic cell subtypes prior to, and during, priming drives the creation of this specialized group of T EFF cells. However, a contribution of signals within NLTs in this process cannot be formally excluded. Specifically, late memory precursor cells that exist in skin 14 days after viral skin infection have been reported to locally receive TGFβ induced signalling, after which these cells are able to rejoin the circulation 64 . It is presently unknown at what rate T cells egress from inflamed tissues at early stages of the immune response, and it will be of interest to determine whether, and to what extent, signals within NLTs can contribute to the production of the circulating T RM cell poised T cell pool.

Signals provided by the dendritic cell subtypes described above may imprint an enhanced T RM cell forming pro pensity in T cells by promoting two different biologi cal properties. First, dendritic cell derived signals may prime T cells for T RM cell fate by enhancing the ability of T cells to accumulate in tissues through either increased tissue entry or tissue retention (fIg. 2a) ; for instance, by driving heightened expression of relevant chemokine receptors 83, 84 , integrins and other adhesion molecules 27 . Related to this, the observation that enhancement of tissue entry or inhibition of tissue egress increases the T RM cell pool size 52, 85 implies that migration and reten tion do represent bottlenecks in T RM cell generation. In addi tion, heightened expression of the chemokine recep tors CCR8, CCR10 and CXCR6 by circulating T EFF cell clones responding to skin inflammation is associated with heightened T RM cell formation in the skin 76 . Second, signals provided by dendritic cells may also promote T RM cell lineage decisions by shaping an epigenetic and transcriptional landscape that makes cells commit more readily to the T RM cell lineage upon encounter of signals within the tissue micro environment (fIg. 2b) . Such vari able responsiveness to T RM cell inducing signals within the pool of T EFF cells is exemplified by the observation that exposure to TGFβ can either induce the expression of CD103 or induce apoptosis in some T EFF cells 66, 86 .

Numerous signals within lymphoid tissues have been identified that help skew T cells towards the T RM cell

Enhancing the intrinsic capacity of a cell to give rise to a particular cell lineage through the induction of epigenetic and/or transcriptional changes.

A state that skews the differentiation potential of T cells towards the tissue resident memory T cell (T rM cell) lineage.

www.nature.com/nri lineage through either of the above mentioned mecha nisms. TGFβ, an immune modulator that promotes T RM cell formation by acting locally at the tissue site 64, 65 , can also steer T RM cell differentiation within lym phoid tissues, both in the absence and the presence of infection. In the absence of foreign antigen, TGFβ activation by migratory dendritic cells in lymph nodes has been shown to induce epigenetic reprogramming of naive T cells, resulting in enhanced accessibility of signature T RM cell genes, such as Itgae and Ccr8, and to modu late the accessibility of target genes of tran scription factors that are involved in T RM cell differen tiation 82 . Such TGFβmediated conditioning of naive T cells was found to be essential for the differentiation of their progeny into T RM cells upon skin infection, but was dispensable for T CIRCM cell formation 82 . Notably, this TGFβ dependent poising of naive T cells towards the T RM cell fate is rever sible, implying that naive T cells require periodic TGFβ signalling to maintain their ability to differentiate into T RM cells. This suggests that naive T cells may vary in their T RM cell poised state, depending on the level or frequency of prior TGFβ encounter, potentially explaining the clonal variation in T RM cell forming capacity that has been observed 76, 77 . Emerging tools that allow for the parallel determination of the epigenetic state of cells at a particular point in time and assessment of their ultimate fate at a later stage could be of major value to link epigenetic heterogeneity in the naive T cell pool to T RM cell differentiation potential 87 .

In the presence of foreign antigen, TGFβ has also been shown to promote the induction of a T RM cell poised state. Upon TCR mediated activation, T cells rapidly down regulate TGFβ receptor expression -perhaps to reduce the immunosuppressive effects of TGFβ -but regain expression around 24 h later 88, 89 . Borges da Silva et al. have shown that such TGFβ receptor re expression by T EFF cells in lymphoid tissues of mice is induced by P2RX7, an extracellular receptor that senses ATP. Interestingly, as a result of their insensitivity to TGFβ, P2rx7 -/early effector T cells in the spleen display diminished Itgae and elevated Eomes expression 89 , two characteristics that are negatively correlated with a T RM cell poised state 14, 76 , in line with the diminished T RM cell forming capacities of these cells. It should be noted that lack of P2rx7 does not affect TGFβ recep tor expression on naive T cells, suggesting that the TGFβ mediated T RM cell fate conditioning that occurs prior to antigen encounter remains unaffected. Although the authors demonstrated that the lack of P2rx7 also nega tively influenced the T RM cell pool size within the small intestine 89,90 , Stark et al. did not observe an effect of P2rx7 deficiency on T RM cell forming capacity of T cells within the same tissue. 91 . As TGFβ signalling is vital for T RM cell differentiation in the gut 51,68 , mechanisms inde pendent of the ATP-P2RX7 axis may exist that ensure TGFβ receptor re expression.

A role for TGFβ in stimulating T RM cell differentia tion during priming has also been described for human T cells. Specifically, the preferential induction of a T RM cell like transcriptome by human CD11c + dendritic cells marked by CD1c and CD163 expression has been explained by their ability to provide active TGFβ during T cell priming 78, 79 . It is noted, however, that an inability of mouse CD11c + dendritic cells to activate TGFβ dur ing T cell priming does not impair mouse skin T RM cell development 82 , suggesting that the TGFβ signal that prepares cells for T RM cell fate during priming in mice is provided by another cell source.

The cytokines IL15 and IL12, and the co stimulatory molecule CD24 -three signals provided by BATF3 + dendritic cells during T cell priming -have been shown to be essential for the differentiation of mouse skin and mechanisms through which mTORC1 steers T RM cell fate decisions are unknown, it is plausible that mTORC1 and other downstream signalling molecules induced by IL15, IL12 and CD24 signals mediate T RM cell forma tion through the induction of molecular networks that also drive terminal effector and T EM cell lineage commit ment. Specifically, studies focusing on the formation of circulating T cell subsets have shown that IL12 (rEf. 99 ) and CD24 (rEf. 81 ), provided by priming dendritic cells, and elevated T cell intrinsic mTORC1 activity 98 strongly favour terminal effector and T EM cell differentiation over T CM cell differentiation, suggesting substantial parallels between creation of the T RM cells and the terminally differentiated T cell lineages. Nevertheless, T RM cells dis play a significant level of multipotency 32 , highlighting that these cells cannot be considered terminally diffe rentiated. T CM cell precursors are protected from termi nal differentiation by the anti inflammatory cytokine IL10, which reduces their sensitivity and exposure to inflammatory stimuli 100 . By analogy, it may be speculated that periodic TGFβ signalling in lymphoid tissues could 'rescue' T RM cell poised T EFF cells from terminal diffe rentiation. In such a model, T RM cell forming potential is coupled to the prevention of terminal differentiation of cells that would otherwise contribute to the T EM cell and terminal effector cell pools (fIg. 3) .

In addition to cytokines and co stimulatory signals, metabolites that are synthesized in processes mediated by dendritic cells also play a major role in promoting T RM cell formation, by driving the expression of tissue homing molecules. Specifically, work over the past years has demonstrated that the expression of certain homing markers on T cells is influenced by the route of patho gen entry into the body 64, [101] [102] [103] and that this effect is, at least partly, due to a variation in availability of mole cular compounds that can be processed by dendritic cells at different lymphoid tissue sites. For example, dend ritic cells can metabolize vitamin D3 -a compound that is abundantly present in the skin -into its active form, and this metabolite suppresses the gut homing programme in T cells, at the same time as inducing the expression of the chemokine receptor CCR10 that allows skin homing 104 . Vice versa, dendritic cells located in gut associated lymphoid tissue can convert vitamin A into retinoic acid, thereby driving T cell expression of the gut homing molecules CCR9 and α4β7 (rEfs 105, 106 ). Collectively, these data illustrate that the differential encounter of cytokines, co stimulatory molecules and metabolites within lymphoid tissues can induce a bias with regards to the T RM cell forming potential within the T EFF cell pool (fIg. 3) . In addition, the idea that the molecular signals present at various priming sites can differentially affect the nature of T RM cell poised T cells implies that recently activated T cells are not primed as a 'universal' T RM cell precursor but are primed to form T RM cells at specific anatomical sites.

Although it is clear that T cells can undergo condition ing that increases their potency to develop into T RM cells at very early stages of the immune response, while still located in lymphoid tissues 80 

Overview of signals within lymphoid tissues that affect the ability of T cells to form CD8 + tissue resident memory T cells (T RM cells) in mouse models. Prior to antigen encounter, naive T cells require periodic TGFβ signalling to adopt and retain a T RM cell-poised state. Upon infection, priming by BATF3 + dendritic cells, which provide IL-15, IL-12 and CD24 signalling, biases T cells to form T RM cells. Presence of tissue-derived factors, such as derivatives of vitamin A and vitamin D, during priming can stimulate the expression of tissue-specific homing molecules, thereby guiding T RM cell-poised T cells to the relevant affected tissues. The presence of TGFβ during priming further maintains the T RM cellpoised state, and it may be proposed that in the absence of TGFβ, T cells primed by BATF3 + dendritic cells are prone to give rise to the CD8 + effector memory T cell (T EM cell) and terminal effector T cell lineages. T CM cell, CD8 + central memory T cell. lung T RM cells, whereas these signals are dispensable for T CIRCM cell formation 80 . However, how these signals promote T RM cell programming is less well understood. Similar to TGFβ, IL12 drives the expression of CD49a (Itga1), a T RM cell associated integrin that shows hetero geneous expression in circulating T EFF cells 92 , and of which elevated transcript levels mark T EFF cell clones with heightened capacity to form T RM cells 76 . Although CD49a is not required for the initial establishment of a T RM cell pool in the skin, the expression of this integrin is vital for long term T RM cell persistence and locomotion 92, 93 . Whether early stage CD49a expression induced by lymphoid derived TGFβ and IL12 signalling affects the ability of mature T RM cells to persist in tissues is unclear. Both IL12 and IL15 have been shown to drive the activation of the mTORC1 protein complex 94, 95 . This observation may explain the effect of these cytokines on T RM cell formation, as inhibition of mTORC1 activity during T cell priming reduces T RM cell formation due to a reduced ability of T EFF cells to migrate to the gut epithe lium and to express CD103, while enhancing their ability to form T CIRCM cells [95] [96] [97] . Directly following T cell prim ing, T cells show variable levels of mTORC1 activity 98 , and it may be proposed that the level of mTORC1 activity may be used to identify T cells biased towards either the T RM cell or T CIRCM cell lineage. Although the exact www.nature.com/nri programmes that underpin this heightened potential have not been identified. Notably, multiple transcription factors have been described that coordinate the develop ment of T RM cells, and to better understand how T RM cell lineage conditioning is regulated within lymphoid tissues, it is useful to examine whether the transcription factors that are known to affect T RM cell development could be regulating T RM cell differentiation already prior to tissue infiltration.

T bet (encoded by Tbx21), EOMES (Eomesodermin, encoded by Eomes) and TCF1 (encoded by Tcf7) are transcription factors that are abundantly expressed by subsets of circulating T cells but are not or are only mini mally expressed by T RM cells in NLTs 17, 52, 62, 107 . Early pois ing towards T RM cell fate is associated with the expression of T bet 80 , and mature T RM cells also require low level T bet expression to allow IL15 receptor cell surface expression 62, 108 . However, higher levels of T bet negatively affect TGFβ receptor expression and, hence, the ability of T cells to form CD103 + T RM cells 62, 109, 110 . Similarly, EOMES is essential for T CIRCM cell formation 108,111 but also counteracts the generation of T RM cells by reducing the expression of the TGFβ receptor 62 . TCF1 is a tran scriptional regulator that coordinates early fate decisions in response to both acute 112 and chronic 113, 114 infections. It can block TGFβ induced CD103 expression through direct interaction with the Itgae locus, and ablation of this transcription factor enhances the formation of lung T RM cells in mouse models 115 . The observation that cir culating T EFF cell clones poised for T RM cell fate display diminished expression of these three transcription factors 76 suggests that the levels of T bet, EOMES and TCF1 may control early stage T RM cell lineage decisions within the lymphoid compartment. As a side note, TGFβ signalling suppresses the expression of these three transcription factors 62, 115 , and IL12 signalling can induce transcriptional repression of both Eomes and Tcf-7 (rEfs 94, 116, 117 ). In humans, evidence for the exis tence of a circulating pool of T RM cell poised T EFF cells, marked by diminished expression of the aforementioned transcription factors as observed in mice 76 , is currently lacking. However, data sets describing single cell gene or protein expression of large numbers of CD8 + T cells in the blood of human subjects who have been recently infected or vaccinated could serve as valuable resources to study their presence 118-120 . Mathew et al. described a pool of cycling EOMES low TBET low TCF1 low T cells that were enriched in individuals infected with SARS CoV2, compared with healthy individuals or individuals who have recovered from COVID19 (rEf. 119 ). To test whether this CD8 + T cell population harbours height ened T RM cell forming capacity in humans, it would be interesting to match the TCR repertoire of this cell pool to that of other blood derived T EFF cell subsets and to the TCR repertoire of mature T RM cells derived from tissue biopsies.

In addition to the transcription factors that repress T RM cell differentiation, numerous transcriptional regu lators including RUNX3, BLIMP1 and its homologue HOBIT, BHLHE40, and NR4A1 have been shown to positively influence T RM cell formation. Although RUNX3 has also been shown to promote T CIRCM cell generation, ablation of RUNX3 affects the T RM cell pool more severely than the T CIRCM cell pool 49, 121 . Additional evidence for a dominant role of RUNX3 in the genera tion of the T RM cell subset over the T CIRCM cell pool comes from the observations that T EFF cells in tissues display increased expression of RUNX3 compared with circu lating T EFF cells 48 , and that forced expression of RUNX3 in activated T cells results in increased expression of core T RM cell signature genes and decreased expression of T CIRCM cell related genes 49 . As RUNX3 has been shown to influence gene expression in recently primed T cells 121 , it is plausible that RUNX3 already aids T RM cell forma tion at a very early stage of the immune response, prior to tissue entry.

BLIMP1 promotes T RM cell formation in various tissues, in part by directly suppressing the expres sion of Tcf7 as well as by suppressing Klf2, Ccr7 and S1pr1 74 , genes that encode proteins that promote tissue egress, thereby inhibiting the formation of the T CM cell lineage 73 . Although genetic deletion of Blimp1 dimin ishes T RM cell formation in the lung, it does not affect the number of T RM cells in the gut and skin, potentially due to activity of the BLIMP1 homologue HOBIT, which shares the ability to suppress the expression of tissue egress promoting genes 74 . However, gut T RM cells that do form in the absence of BLIMP1 are defective in granzyme B production 122 , highlighting that BLIMP1 is important to support the acquisition of some aspects of T RM cell function. With respect to a potential role of BLIMP1 in determining T RM cell fate in the circulat ing T cell pool, we note that circulating T EFF cell clones with enhanced T RM cell forming capacity are marked by elevated transcript levels of Gzmb, which encodes granzyme B, relative to other memory precursor cells 76 . As BLIMP1 is an essential driver of Gzmb expression within the circulating T EFF cell pool 122, 123 , this relation ship may conceivably reflect a moulding of the circula ting T EFF cell population into a T RM cell poised state by BLIMP1. In support of this hypothesis, dendritic cell derived IL15 and IL12 within lymphoid tissues are required to induce a T RM cell poised state 80 and these signals are also known drivers of BLIMP1 expression in early effector T cells 95, 123 . Within the mouse CD8 + T cell lineage, Hobit is highly expressed by T RM cells, but not or only minimally by T CM cells and T EM cells 74, 124 . Whether circulating mouse effector T cells at any stage express HOBIT has not been reported. On the other hand, abundant expression of HOBIT has been described in circulating human effector like T cells 17, [125] [126] [127] , but unlike in mouse T RM cells, HOBIT does not prominently mark human T RM cells 17, 128 . Thus, whether HOBIT plays a role in both mouse and human T RM cell formation prior to tissue entry remains undefined.

Marked expression of the transcriptional regulators BHLHE40 and NR4A1 has been observed in T EFF cells in tissues and in mature T RM cells in both mice and humans, and genetic deletion of these factors selectively hinders the formation of T RM cells in mice 49, 129, 130 . In addition, NR4A1 expression has been reported within the circu lating pool of CD8 + T EFF cells, where it functions as a sup pressor of cell division and effector differentiation [131] [132] [133] . BHLHE40 expression has been observed within the pool Nature reviews | Immunology 0123456789();: of effector CD4 + T cells 134, 135 , but BHLHE40 expression by circulating CD8 + T EFF cells is less well described. More research is required to investigate whether BHLHE40 and NR4A1 are involved in T RM cell lineage decisions within lymphoid tissues or selectively act once T cells have seeded affected tissues.

Although differential expression of transcription fac tors, such as T bet and RUNX3, is likely to form a major driver of T RM cell lineage divergence, target gene acces sibility is thought to represent a second layer of control. T RM cells are characterized by a distinct epigenetic state as compared with T EM cells and T CM cells 25, 31, 32, 38 , and diffe r ences in the epigenetic landscape are already apparent at the T RM precursor cell stage. For instance, a distinct set of RUNX3 target genes are accessible in T EFF cells localized in the gut epithelium and in the spleen of lympho cytic choriomeningitis virus (LCMV) infected mice 49 . Notably, an enhanced RUNX3 target gene accessibility has been described in T RM cell poised naive T cells, coinciding with a reduced accessibility of T box target genes 82 . Furthermore, RUNX3 has been reported to induce global chromatin changes shortly after T cell activation, enhancing accessibility of BLIMP1 target sites and also inducing BLIMP1 expression 121 . Together, these data suggest a mechanism for early T RM cell lineage poising that relies on both the expression of certain tran scriptional regulators and the increased accessibility of their target genes.

T Rm cell precursors during reinfection The data described above document the existence of circulating T cells that are poised to give rise to T RM cells after a primary infection. Remarkably, recent studies have uncovered that a similar population can also be detected upon recurring infection; however, these cells have a different origin. Upon local reinfection, T RM cells can proliferate -and whereas part of the offspring remain at the tissue site 136, 137 , some of these cells may leave the tis sue site. In addition to the observation that such 'ex NLT' T RM cell offspring can take up permanent residence in tissue draining lymph nodes 30, 138 , a recent study revealed that skin T RM cell derived T EFF cells that are marked by the T RM cell associated proteins CD103 and CD49a can be detected within the circulation 32 . Furthermore, it was shown that the offspring of intravenously trans ferred T RM cells possesses a high propensity to home to the tissue of origin and to again differentiate into res ident memory cells upon infection. Combined, these observations suggest that T RM cell derived offspring that naturally egress from tissues may also be primed to again form T RM cells 32 . Evidence that T RM cells can pro duce circulating offspring that possess a heightened potential to again form T RM cells has also been obtained in two other studies. Work by Behr et al. demonstrated that gut derived T RM cells that were engrafted into liver tissue produced circulating T EFF cells upon LCMV infection, which preferentially formed T RM cells in gut tissue 124 . Furthermore, Klicznik et al. demonstrated that CD4 + tissue resident memory T cells derived from human skin xenografts can egress from the tissue, form CD103 + cir culating T cells and, subsequently, form tissue resident memory T cells at distant skin tissue sites 139 . It has not been resolved which factors drive the re entry of a selec tion of T RM cell derived offspring into the circulation. Conceivably, the type or activation state of the APCs encountered locally could play a critical role in this process, as distinct types of APCs can differentially affect the gene expression profile of activated T RM cells, including genes involved in tissue egress 140 .

It has become increasingly clear that cues within lym phoid tissues can condition T cells, at the level of both naive and early effector T cells, to preferentially develop into T RM cells, and the presence of T RM cell poised T cells within the circulating memory precursor cell pool reflects the result of these processes (fIg. 4) . It is of interest to note that evidence supporting the existence of a circulating precursor population in lymphoid organs that has an increased propensity to take up residence in NLTs is not restricted to the CD8 + T cell compartment. Specifically, recent work has revealed the existence of CD4 + regula tory T cells within lymphoid tissues that epigenetically and transcriptionally resemble regulatory T cells within NLTs, and such cells are fated to traffic to NLTs and, sub sequently, take up residency in peripheral tissue [141] [142] [143] . As the molecular mechanisms used to instruct a 'tissue fate' in different subsets of circulating leukocytes are likely to share common themes, the parallel study of resi dency promoting and inhibiting programmes in different cell subsets may be attractive.

The processes that are involved in the creation of the circulating T RM cell poised T cell pool will, at least partly, differ depending on the route of infection. Specifically, a number of the molecular and cellular cues that induce a T RM cell poised state within lymphoid tissues find their origin in the associated NLTs (for example, CD103 + migratory dendritic cells, vitamin D, vitamin A) 80, 82, 144 .

The importance of such crosstalk may also be reflected T RM cell-poised T cell Circu lating CD8 + tissue resident memory T cell (T RM cell)-poised and CD8 + circulating memory T cell (T CIRCM cell)-poised memory precursor T cells share the classical memory precursor phenotype IL-7Rα hi KLRG1 low . However, numerous other properties could be used to distinguish the two groups of memory precursor cells 76, 82, 89, 96 . Arrows depict relative level of activity or expression. Data on BLIMP1 and RUNX3 are indirect. by the fact that no T cells that transcriptionally mimic T RM cells were detectable within the circulating T EFF cell pool after systemic LCMV infection 48 . It should be noted, however, that T RM cells do form in various NLTs following systemic LCMV infection, indicating that although tissue derived signals present at the priming site may promote T RM cell formation, such signals are not always essential. In future work, it will be valuable to compare the formation of, and properties of, circula ting T RM cell precursors in response to local infections at different tissue sites, to better understand the role of different tissue cues in the creation of this cell pool.

As a final area of future research, our current under standing of T RM cell fate conditioning within lymphoid tissues is predominantly based on work that tests the contribution of individual signals at a particular point in time, through the use of mouse models that are deficient in such signals. It will be attractive to complement this type of perturbation studies with studies that record the signals that cells receive, to test which signals are most predictive of future cell fate. Although a comprehensive monitoring of signalling events and subsequent changes in epigenetic and transcriptional states is unlikely to become feasible in the coming years, numerous pre viously established or recently developed tools will be valuable for this purpose. Specifically, methods that record -preferably quantitatively -the historic exposure to external signals, such as CRISPR based approaches that induce genomic modifications upon the reception of a signal of interest 145 , are likely to serve as a useful approach to monitor the relationship between early signals and subsequent T RM cell forma tion. Similarly, the use of reporter systems in which the expression of genes of interest leads to stable genetic or protein marks 75, 124 could provide insights into the gene expression profile that marks T RM cell precursors before they reach the tissue site. Finally, a recently developed transposon based tool that 'immortalizes' the pattern of historic interactions of transcription factors with avail able DNA target sites 87 may be of significant value to the epigenetic state of early effector T cells to the memory T cell state they assume later on.

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Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

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L.K. researched data for the article. L.K. and T.N.M. discussed content and wrote the initial concept. L.K., D.M. and T.N.M. reviewed and edited the manuscript.

The authors declare no competing interests.

Nature Reviews Immunology thanks Benjamin A. Youngblood and the other, anonymous, reviewers for their contribution to the peer review of this work.

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