key: cord-0768337-2kov2df2
authors: Chen, Zeyu; John Wherry, E.
title: T cell responses in patients with COVID-19
date: 2020-07-29
journal: Nat Rev Immunol
DOI: 10.1038/s41577-020-0402-6
sha: 6c9a07eaa554926062a9c1428c088db8a2393b79
doc_id: 768337
cord_uid: 2kov2df2

The role of T cells in the resolution or exacerbation of COVID-19, as well as their potential to provide long-term protection from reinfection with SARS-CoV-2, remains debated. Nevertheless, recent studies have highlighted various aspects of T cell responses to SARS-CoV-2 infection that are starting to enable some general concepts to emerge.

COVID-19 caused by SARS-CoV-2 infection is a global pandemic, with more than 15.8 million infections and more than 641,000 deaths as of 25 July 2020, according to the COVID-19 Map of the Johns Hopkins Coronavirus Resource Center. SARS-CoV-2 infection can result in a range of clinical manifestations, from asymptomatic or mild infection to severe COVID-19 that requires hospitalization. Patients who are hospitalized often progress to severe pneumonia and acute respiratory distress syndrome (ARDS) [1] [2] [3] . Although relatively little is known about the immunology of individuals who are asymptomatic or individuals with mild disease who do not require hospitalization, recent studies have revealed important insights into the immune responses of patients who are hospitalized. Similar to other respiratory viral infections, adaptive immune responses [4] [5] [6] [7] [8] [9] , particularly of T cells 6, 8, 10 , have a prominent role in SARS-CoV-2 infection. However, it remains unclear whether T cell responses are helpful or harmful in COVID- 19 , and whether T cell responses are suboptimal and dysfunctional or excessive, with evidence having been provided for both ends of the spectrum.

Here, we summarize some of the recent data on conventional T cell responses in COVID-19, noting, however, that emerging data also highlight impacts on other lymphocyte populations, including B cells 4, 8, 11 , innate lymphoid cells 4 , natural killer cells 4, 11 , mucosa-associated invariant T cells 4 and γδT cells 11 . We highlight some of the key observations made for conventional αβ CD8 + and CD4 + T cells in COVID-19, including the prominent lymphopenia typically occurs for only 2-4 days around symptom onset and rapidly recovers 15 . By contrast, COVID-19-associated lymphopenia may be more severe or persistent than in these other infections and seems to be more selective for T cell lineages. It is possible that the peripheral lymphopenia observed in patients with COVID-19 reflects recruitment of lymphocytes to the respiratory tract or adhesion to inflamed respiratory vascular endothelium. However, although autopsy studies of patients' lungs and single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid do identify the presence of lymphocytes, the lymphocytic infiltration is not excessive 5, 16 . In addition, a recent scRNA-seq analysis of the upper respiratory tract from patients with COVID-19 showed that there was a markedly decreased contribution of cytotoxic T lymphocytes in patients with severe disease compared with those with moderate disease 9 . In severe disease, lymphopenia may be associated with high levels of IL-6, IL-10 or tumour necrosis factor (TNF) 6, 10, 14 , potentially through a direct effect of these cytokines on T cell populations 17, 18 and/or indirect effects via other cell types, such as dendritic cells 19 and neutrophils 20, 21 . Hyperactivation of T cells or high levels of expression of pro-apoptotic molecules, such as FAS (also known as CD95) 8 , TRAIL or caspase 3 (ref. 11 ), could also contribute to T cell depletion.

Thus, although the mechanisms of lymphopenia in COVID-19 remain incompletely understood, the reduction in the number of T cells, in particular, in the periphery is a prominent feature of many individuals with severe disease. It remains unclear why the lymphopenia is T cell biased and perhaps specifically CD8 + T cell biased. In animal models, lymphopenia can augment T cell activation and proliferation 22 . Therefore, determining how lymphopenia in patients with COVID-19 might impact T cell hyperactivation and, potentially, immunopathology is an important future goal, as therapeutics such as IL-7 could be beneficial in this regard.

Early studies of small numbers of patients, or sometimes even a single patient, reported alterations in the activation and/or differentiation status of CD8 + T cells in observed in patients with severe disease, relevant features of CD8 + versus CD4 + T cell responses in patients who are hospitalized, features of T cell differentiation that may be altered and current data on whether the overall magnitude of the T cell response in patients with COVID-19 is insufficient or excessive and how these features may relate to disease. Finally, we discuss emerging data on SARS-CoV-2-specific T cells found in patients who have recovered from COVID-19 and the implications for T cell memory. In this rapidly emerging field, we summarize the most recent studies that have addressed T cell responses in COVID-19. Some of these are as yet only available on preprint servers and conclusions from non-peer-reviewed data should be treated with caution. A summary of the data sets that are published versus those available as preprints is provided in Table 1 to aid the reader in establishing the weight of evidence for particular features.

One prominent feature of SARS-CoV-2 infection is lymphopenia 1, 6, 12, 13 . Lymphopenia is associated with severe disease 10,12,13 but is reversed when patients recover 4, 12 . In some patients, lymphopenia has been reported to affect CD4 + T cells, CD8 + T cells, B cells and natural killer cells 4, 6 , whereas other data suggest that SARS-CoV-2 infection has a preferential impact on CD8 + T cells 8, 9, 14 . Transient lymphopenia is a common feature of many respiratory viral infections, such as with influenza A H3N2 virus, human rhinovirus or respiratory syncytial virus, but lymphopenia in these other infections Flow cytometry T cell lymphopenia in patients compared with healthy controls, with an increased ratio of CD4 + T cells to CD8 + T cells; increased proportion of terminally differentiated or senescent CD8 + T cells in patients, with a reduced proportion of IFNγ-producing cells; tocilizumab improves lymphocyte counts (n = 5) 14 30 healthy, 55 mild disease, 13 severe disease PBMCs Flow cytometry Stronger T cell lymphopenia in severe disease than in mild disease or healthy controls, with recovery of T cell numbers in convalescent individuals; reduced levels of multiple cytokines in CD8 + T cells in disease groups, with higher levels of NKG2A expression than healthy controls 23 6 healthy, 10 mild disease, 6 severe disease PBMCs Flow cytometry Increased cytotoxicity but decreased cytokine secretion of T cells, particularly CD8 + T cells, in severe disease compared with mild disease; CD8 + T cells in severe disease express more inhibitory receptors 24 Case report, multiple time points

Flow cytometry ICOS + PD1 + circulating T FH cells increase during recovery; activated CD4 + and CD8 + T cells peak at day 9 post disease onset and decline after recovery 26 www.nature.com/nri severe COVID-19 ( fig. 1a ). For example, there is evidence of terminally differentiated T cells or possibly exhausted T cells in severe disease, with reported increases in expression levels of the inhibitory receptors PD1, TIM3, LAG3, CTLA4, NKG2A and CD39 (refs 4,8,10,11,23,24 ). However, expression of these receptors could also reflect recent activation, and it is not clear whether the T cells in patients with COVID-19 are exhausted or just highly activated. By contrast, at least one blood scRNA-seq study has reported limited expression of inhibitory receptors by CD8 + T cells in patients with COVID-19 compared with healthy controls 7 . In one report, CD8 + T cells from patients with severe COVID-19 had reduced cytokine production upon stimulation 23 . Alternatively, other data suggest that CD8 + T cells might have a hyperactivation signature, including high levels of expression of natural killer cell-related markers and increased cytotoxicity 4, 23, 25 . Some of these studies imply the presence of an overaggressive CD8 + T cell response or a hyperactive state in patients with COVID-19 (ref. 25 ). Increased numbers of CD38 + HLA-DR + activated CD8 + T cells or Ki67 + proliferating CD8 + T cells were also responses 5, 16 , and recent scRNA-seq data from the upper respiratory tract imply that interactions occur there between epithelial cells and cytotoxic T lymphocytes, in particular through an interferon-γ (IFNγ) axis 9 . Indeed, more robust clonal expansion of CD8 + T cells in peripheral blood 28 or bronchoalveolar lavage fluid 5 may be associated with milder disease or recovery, although it is not clear whether this CD8 + T cell clonal expansion is the cause or consequence of the disease recovery. Last, there is evidence of SARS-CoV-2-specific CD8 + T cells in patients who have recovered, which provides evidence not only of virus-specific CD8 + T cell responses but also of CD8 + T cell memory in many convalescent patients [29] [30] [31] [32] . The precise role of these virus-specific CD8 + T cells in control of initial acute SARS-CoV-2 infection and their capacity to protect from future infection remain to be determined.

CD4 + T cell responses in COVID-19 Similar to CD8 + T cells, there is evidence of functional impairment and increased expression of activation and/or exhaustion markers by CD4 + T cells in patients with COVID-19 ( T cell reactivity to SARS-CoV-2 also detected in non-exposed donors, with potential cross-reactivity to other common cold coronaviruses 29 14 convalescent PBMCs Flow cytometry CD4 + and CD8 + T cells from convalescent patients respond to SARS-CoV-2 epitopes 30 16 healthy, 28 36 . A population of CD4 + T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-6 has also been reported in patients with COVID-19 (ref. 37 ), although T cells do not typically produce IL-6. Regulatory T cells 36 and ICOS + CD38 + circulating T follicular have suggested that CD8 + T cell activation might be greater than CD4 + T cell activation, as defined by activation markers such as CD38 and HLA-DR 26, 33, 34 . However, another study identified a subset of patients with higher levels of CD4 + T cell activation who possibly do worse clinically 8 . One report has described a higher proportion of IFNγ-producing T helper 1 (T H 1)-like cells in patients with moderate disease than in patients with severe disease 13 www.nature.com/nri helper (activated cT FH ) cells 8 may also be altered in patients with COVID-19, with increased numbers of activated cT FH cells in some settings perhaps connected to a reported increase in the number of circulating plasmablasts 4 . Lymphopenia also affects CD4 + T cells, although some studies suggest that the impact is less than that for CD8 + T cells 8, 38 . It remains to be determined how lym phopenia might relate to CD4 + T cell activation and/or dysfunction. Moreover, in addition to memory CD8 + T cells, patients who have recovered from SARS-CoV-2 infection have virus-specific memory CD4 + T cells [29] [30] [31] [32] , which bodes well for the possibility of T cell memory and, perhaps, protective immunity. In individuals who recovered from mild COVID-19, CD4 + T cells gained a typical memory phenotype with high levels of expression of IL-7Rα (ref. 32 ). Interestingly, cross-reactive memory CD4 + T cells are also found in subjects who have never been exposed to SARS-CoV-2 (ref. 29 ). It is unclear how these pre-existing memory CD4 + T cells, which are presumably generated in response to human endemic coronaviruses, affect immunity or pathology upon SARS-CoV-2 infection. There are other settings in which the presence of memory CD4 + T cells in the absence of effective CD8 + T cells or antibodies can cause pathology 39 . Thus, CD4 + T cell responses are present in patients with COVID-19 and perhaps form memory following resolution of the disease. Whether CD4 + T cells responding in acute infection with SARS-CoV-2 are functionally impaired or hyperactivated, and how these responses relate to disease outcome, remain important unanswered questions.

Most acute viral infections in humans induce the activation and proliferation of both CD4 + T cells and CD8 + T cells, so SARS-CoV-2 infection may not be unique in this regard. However, hyperactivation or hypoactivation of T cells, or skewing towards an ineffective differentiation state (for example, T H 17 cells, exhausted T cells or terminally differentiated T cells), might not be optimal in some patients with COVID-19. Several features that have been described in patients with severe COVID-19including high levels of systemic cytokines or chemokines, most notably IL-6, CXCL8, CXCL9 and CXCL10 (refs 8,11,40 ), or delayed or defective type I interferon responses 41could potentially skew T cell responses. The potential type I interferon deficiency described in patients with COVID-19 is consistent with a recent observation of reduced numbers of plasmacytoid dendritic cells 11 . This observation, however, contrasts with the robust and consistent upregulation of the interferon-inducible chemokine CXCL10 observed in one patient cohort 11 , perhaps owing to non-interferon inducers of expression of this chemokine.

Another key gap in our understanding is the relationship between viral load and the immune response. Viral load could have a major impact on the magnitude and quality of the T cell response, and future studies that quantify virus replication should provide context for understanding evolving T cell responses during SARS-CoV-2 infection.

A key feature of patients with COVID-19 is the enrichment for co-morbidities such as hypertension and diabetes 42 (see next section), but it remains to be defined how an individual patient's background 'immune health' landscape shapes responses to SARS-CoV-2 infection. Although lymphopenia is not a unique feature of SARS-CoV-2 infection 43 , it may be more prolonged in patients with COVID-19, and lymphopenia-induced proliferation can clearly affect T cell differentiation and activation; however, the contribution of lymphopenia to T cell differentiation in patients with COVID- 19 has not yet been investigated.

Co-morbidities such as cardiovascular disease 44, 45 , diabetes 42 and obesity 46 are some of the most common underlying conditions associated with worse clinical outcome and severe COVID-19. Moreover, older patients experience greater clinical severity of COVID-19 (refs 1,47 ), males may experience more severe disease than females 1,47 and genetic variations, including the ABO blood type 8, 48, 49 , have been reported to affect the clinical outcomes for patients with COVID-19. However, how these co-morbidities are associated with T cell responses during COVID-19 remains largely unknown.

Advanced age is a common co-morbidity for severity of disease during respiratory viral infections, and disease severity may be associated with altered T cell responses 50, 51 . Ageing affects T cell repertoire diversity 52 , both for CD4 + T cells 53 and for CD8 + T cells 54 . This age-related reduction in T cell clonal diversity is associated with impaired responses to viral infections such as influenza 55 . Advanced age can also be associated with T cell senescence, which perhaps contributes to ineffective responses to infections 56, 57 . However, senescent T cells may also paradoxically be pro-inflammatory and therefore perhaps contribute to immunopathology. Older patients experience more severe lymphopenia during COVID-19 (ref. 10 ), although it is not clear whether ageing-associated lymphopenia is causal to disease severity or vice versa.

Men with COVID-19 have higher rates of hospitalization and mortality than women 58 , and among severe cases of disease, men have more severe lymphopenia 59 . There may also be a bias to stronger CD4 + and CD8 + T cell activation in women with COVID-19 (ref. 60 ). It is unclear whether these sex biases relate to X chromosome-encoded immune genes 58 and/or the role of sex hormones in regulating immune responses 61 . Nevertheless, these data highlight the importance of accounting for sex in ongoing clinical trials.

A very high proportion of patients with COVID-19 who are hospitalized have one or more underlying cardiovascular co-morbidities 44, 45, [62] [63] [64] . Moreover, many of the manifestations of severe disease relate to coagulopathies and vascular complications 62, 64 . Even the newly recognized SARS-CoV-2-associated multisystem inflammatory syndrome in children has similarities to Kawasaki disease, which often involves inflammation of the coronary artery 65, 66 . Other viral infections, including Ebola virus and virulent lymphocytic choriomeningitis virus in mice, can cause damage to the vascular endothelium. These viruses infect the vascular endothelium, and T cells can then cause vascular damage by attacking the virus-infected cells [67] [68] [69] . However, disease presentation in these settings is distinct from that for COVID-19, and extensive SARS-CoV-2 infection of the vascular endothelium is unlikely in most patients.

Obesity also contributes to more severe COVID-19 and higher rates of hospitalization 46, 70 , which are perhaps associated with the role of body mass index in cardiovascular health. However, obesity can also directly affect T cell responses to influenza vaccination 71 or infection 72 , and a role for obesity in altering T cell differentiation has been observed in asthma 73 and chronic inflammation 74 . Nevertheless, the precise role of T cells in driving the coagulopathies or inflammation that are characteristic of severe COVID-19 in patients with cardiovascular co-morbidities is unclear.

Finally, a recent genetic association study compared patients with severe COVID-19 and ARDS with healthy controls 49 . Several chemokine receptor genes, including CCR9, CXCR6 and XCR1, and the locus controlling the ABO blood type were identified as being associated with severe disease. Whether these genes are directly or indirectly related to T cell responses in COVID-19, however, remains unknown and needs further investigation.

Thus, although severe COVID-19 is partially characterized by patients with co-morbidities, how these co-morbidities relate to T cell responses remains poorly understood. Causal associations may exist, perhaps connected to some of the underlying genetics. However, it is also possible that certain co-morbidities or pre-existing conditions make patients with severe disease less able to tolerate the severe virus-mediated and immune-mediated pathology associated with SARS-CoV-2 infection.

The published data discussed here indicate that patients with severe COVID-19 can have either insufficient or excessive T cell responses. It is possible, therefore, that disease might occur in different patients at either end of this immune response spectrum, in one case from virus-mediated pathology and in the other case from T cell-driven immunopathology 4 . However, it is unclear why some patients respond too little and some patients too much, and whether the strength of the T cell response in the peripheral blood reflects the T cell response intensity in the respiratory tract and other SARS-CoV-2-infected organs. Some information exists on SARS-CoV-2-specific T cells in patients who are hospitalized, and approaches using activation markers (such as Ki67) likely capture virus-specific T cell responses; recent studies are beginning to fill in this picture by identifying virus-specific CD4 + T cells and CD8 + T cells in acute disease 5, 29, 30 . However, one missing set of information is a careful immune analysis of outpatients who, during acute infection with SARS-CoV-2, are undergoing a 'successful' immune response. Moreover, it will be crucial to incorporate into any model of COVID-19 how the magnitude and quality of T cell responses relate to signals from other parts of the immune system, such as innate cytokines, antigen presentation and myeloid cells. Lastly, the strength of the T cell response may also relate to the stage of disease or infection. Accurately assessing the different 'phases' of acute SARS-CoV-2 infection may also be valuable in interpreting T cell responses.

Thus, future studies should provide insights into how to identify patients at different stages of disease or with different immune response characteristics and then to match them with treatment strategies. Such a precision medicine strategy based on analysis of 'immune health' could be used to better tailor the use of immunostimulatory strategies such as thymosin α1 (ref. 25 ) or type I interferon 75 versus immunosuppressive drugs such as tocilizumab [76] [77] [78] , ruxolitinib 79 or dexamethasone 80 to patients who will receive most benefit. These efforts should be aided by the development of better preclinical models, including human ACE2-expressing mice [81] [82] [83] [84] [85] . It will be interesting in the future to use such models to address key questions including: what is an 'appropriate' profile of T cell activation and differentiation for a successful antiviral response to SARS-CoV-2 without triggering severe pathology; how does viral load or initial inoculum of SARS-CoV-2 impact T cell responses and pathology; how do T cell responses in the blood relate to lung-infiltrating T cells, considering that many respiratory viruses are controlled by tissue-resident immune cells that may not be present in the blood; and what are the molecular mechanisms that support a successful T cell response during SARS-CoV-2 infection?

A key question is whether protective T cell memory can form following either SARS-CoV-2 infection or vaccination. Although data on vaccination will await trial results, early data from patients with COVID-19 who have recovered are promising. Memory CD4 + T cells and CD8 + T cells were detected in 100% and 70% of patients who recovered, respectively 29 . Moreover, memory T cell responses were detected for multiple SARS-CoV-2 proteins, including not only spike protein but also nucleoprotein and membrane protein 31 . Whether these T cells provide protective immunity is unclear, and addressing this question for T cells alone will be confounded by the presence of SARS-CoV-2-specific antibodies in patients who recover. Nevertheless, ongoing analysis of patients who have recovered should provide insights into the protective capacity of immune memory, including humoral and cellular memory, as these individuals are potentially re-exposed to SARS-CoV-2 in the community. Further studies should also define the differentiation state and durability of T cell memory. Moreover, defining how T cell memory forms in patients who experience mild symptoms of COVID-19 versus severe disease will be important. Although evidence of T cell memory to other coronaviruses is encouraging, such immune natural history studies for SARS-CoV-2 will likely be valuable for examining vaccine-induced T cell responses.

The accumulating evidence supports a role for T cells in COVID-19 and probably in the immunological memory that forms following recovery from SARS-CoV-2 infection. Most, although not all, patients who are hospitalized seem to mount both CD8 + and CD4 + T cell responses, and evidence points to possible suboptimal, excessive or otherwise inappropriate T cell responses associated with severe disease. In fact, multiple distinct patterns of T cell response may exist in different patients, which suggests the possibility of distinct clinical approaches tailored to the particular immunotype of a specific patient. Much of the available data on T cell responses in patients with COVID-19 who are hospitalized is still available only in preprint form. This format has been essential for rapid dissemination of information in the setting of pandemic urgency. However, as these studies move through peer review, we should gain increasing confidence and clarity about the nature of T cell responses to SARS-CoV-2 infection. More carefully defining distinct classes of T cell response types in COVID-19 and delineating how pre-existing conditions, co-morbidities, race, 'immune health' status and other variables influence T cell responses should reveal novel opportunities for treatment and prevention.

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Treatment for severe acute respiratory distress syndrome from COVID-19

Comprehensive mapping of immune perturbations associated with severe COVID-19

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

A single-cell atlas of the peripheral immune response in patients with severe COVID-19

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19)

A consensus Covid-19 immune signature combines immuno-protection with discrete sepsis-like traits associated with poor prognosis

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

Clinical and immunological features of severe and moderate coronavirus disease 2019

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

Longitudinal analysis of leukocyte differentials in peripheral blood of patients with acute respiratory viral infections

Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study

IL-10 inhibits human T cell proliferation and IL-2 production

IL-6 trans-signaling-dependent rapid development of cytotoxic CD8 + T cell function

IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression

Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19

Predictive value of the neutrophil-tolymphocyte ratio (NLR) for diagnosis and worse clinical course of the COVID-19: findings from ten provinces in China

Homeostasis of naive and memory T cells

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

Thymosin α-1 protected T cells from excessive activation in severe COVID-19

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

Human effector and memory CD8 + T cell responses to smallpox and yellow fever vaccines

Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing

Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals

Broad and strong memory CD4 and CD8 T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients

SARS-CoV-2-specific T cells exhibit unique features characterized by robust helper function, lack of terminal differentiation, and high proliferative potential

Immunology of COVID-19: current state of the science

Dysregulation of immune response in patients with coronavirus 2019 (COVID-19

Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome

High-dimensional immune profiling by mass cytometry revealed immunosuppression and dysfunction of immunity in COVID-19 patients

Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients

Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia

Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection

Targeted immunosuppression distinguishes COVID-19 from influenza in moderate and severe disease

Imbalanced host response to SARS-CoV-2 drives development of COVID-19

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

Relationship between the ABO blood group and the COVID-19 susceptibility

Genomewide association study of severe Covid-19 with respiratory failure

T-cell biology in aging, with a focus on lung disease

Successful and maladaptive T cell aging

The influence of age on T cell generation and TCR diversity

The cytomegalovirus-specific CD4 + T-cell response expands with age and markedly alters the CD4 + T-cell repertoire

Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense

Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus

Signaling pathways in aged T cells-a reflection of T cell differentiation, cell senescence and host environment

T cell senescence and cardiovascular diseases

Considering how biological sex impacts immune responses and COVID-19 outcomes

Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: a retrospective study of 168 severe patients

Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes

Sex hormones and the immune response in humans

COVID-19 and the cardiovascular system

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Kawasaki-like disease: emerging complication during the COVID-19 pandemic

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic

Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice

Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury

Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care

Obesity and impaired metabolic health in patients with COVID-19

Obesity is associated with impaired immune response to influenza vaccination in humans

Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus

Obesity and asthma: beyond T H 2 inflammation

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

Type 1 interferons as a potential treatment against COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

Tocilizumab treatment in COVID-19: a single center experience

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial

Letter to the editor: efficacy of different methods of combination regimen administrations including dexamethasone, intravenous immunoglobulin, and interferon-β to treat critically ill COVID-19 patients: a structured summary of a study protocol for a randomized controlled trial

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Generation of a broadly useful model for COVID-19 pathogenesis, vaccination, and treatment

A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensinconverting enzyme 2

Acknowledgements Z.C. is supported by grant CA234842 from the National Institutes of Health (NIH). Work in the Wherry laboratory is supported by NIH grant AI082630, the Allen Institute for Immunology and the Parker Institute for Cancer Immunotherapy.

The authors contributed equally to all aspects of the article.

E.J.W. has consulting agreements with and/or is a scientific advisor for Merck, Roche, Pieris, Elstar and Surface Oncology. E.J.W. has a patent licensing agreement on the PD1 pathway with Roche/Genentech. E.J.W. is a founder of Arsenal Biosciences. Z.C. declares no competing interests.

Nature Reviews Immunology thanks Susan L. Swain and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.