key: cord-0757499-dnxqqxni
authors: Menon, Madhvi; Hussell, Tracy; Ali Shuwa, Halima
title: Regulatory B cells in respiratory health and diseases
date: 2021-01-06
journal: Immunol Rev
DOI: 10.1111/imr.12941
sha: cce65f76fc44940de1dd99cadd492e8c51e188ad
doc_id: 757499
cord_uid: dnxqqxni

B cells are critical mediators of humoral immune responses in the airways through antibody production, antigen presentation, and cytokine secretion. In addition, a subset of B cells, known as regulatory B cells (Bregs), exhibit immunosuppressive functions via diverse regulatory mechanisms. Bregs modulate immune responses via the secretion of IL‐10, IL‐35, and tumor growth factor‐β (TGF‐β), and by direct cell contact. The balance between effector and regulatory B cell functions is critical in the maintenance of immune homeostasis. The importance of Bregs in airway immune responses is emphasized by the different respiratory disorders associated with abnormalities in Breg numbers and function. In this review, we summarize the role of immunosuppressive Bregs in airway inflammatory diseases and highlight the importance of this subset in the maintenance of respiratory health. We propose that improved understanding of signals in the lung microenvironment that drive Breg differentiation can provide novel therapeutic avenues for improved management of respiratory diseases.

B cells are an essential part of humoral immune responses in the airways through antibody production, antigen presentation, and cytokine secretion. 1 Although these functions are pivotal in the clearance of invading pathogens and the development of long-term immunity, unrestrained inflammation can cause irreversible damage to tissues. 1 To prevent this, we require mechanisms of suppression that prevent exaggerated immune responses and maintain tissue homeostasis.

In addition to well-established effector functions, a subset of immunosuppressive B cells, known as regulatory B cells or Bregs, contribute to preventing uncontrolled inflammation. 2 Bregs, as negative regulators of the immune system, suppress inflammatory responses via the production of IL-10 and other anti-inflammatory mediators, as well as via direct cell contact. Depending on the disease context, Bregs can be either pathogenic or beneficial; whereas an expansion of Bregs is advantageous in autoimmunity and other chronic inflammatory conditions, increased Breg frequencies can cause detrimental immune suppression in infectious diseases and cancers. 3 The signals required for the induction of Bregs include a combination of toll-like receptor (TLRs) ligands, CD40-ligand (CD40-L), antigens activating the B cell receptor (BCR), co-stimulatory molecules (CD80, CD86), and inflammatory cytokines. 2, 4 Majority of these stimuli can be found in the lung microenvironment, 1,5 supporting an expansion of Bregs in the airways. Moreover, numerical and functional abnormalities in Bregs have been associated with various immune-related lung pathologies, [6] [7] [8] [9] highlighting the importance of this B cell subset in mounting an appropriate immune response in the airways. For these reasons, there is an increased interest in understanding the role of Bregs in respiratory health and disease settings. This review summarizes the role of immunosuppressive Bregs in airway inflammatory diseases, including lung cancer, respiratory infections, allergy, pulmonary fibrosis, and autoimmune pulmonary manifestations, thus emphasizing the importance of this subset in the maintenance of respiratory health.

Over the past decade, studies in experimental animal models and patients with autoimmune diseases have identified multiple Breg subsets exhibiting diverse mechanisms of immune suppression. 3 Evidence suggests that the environmental milieu plays a pivotal role in the induction of Bregs. In addition to TLR, BCR, and CD40 signaling, as well as CD80 and CD86 activation, inflammatory cytokines have been shown to play an important role in expanding immunosuppressive Bregs. 4 For example, exposure to inflammatory cytokines IL-1β and IL-6 has been shown to induce Breg differentiation in a mouse model of arthritis. 10 Moreover, mice with B cell-specific deletion of IL-1R1 or IL-6R displayed reduced Bregs and exacerbated arthritis. Interestingly, the production of IL-1β and IL-6 is modulated by gut bacteria, highlighting an indirect role for microbiota in Breg induction. 10 Other inflammatory cytokines, such as type I interferons (IFN-I), IL-21 and B cell-activating factor (BAFF) have also been shown to play a role in Breg differentiation. [11] [12] [13] [14] Although anti-inflammatory cytokine IL-35 has been shown to expand IL-10-and IL-35-producing Bregs, 15 evidence suggests that IL-35 is itself induced in response to inflammatory stimuli. 16 Of note, activation of STAT3 is important for induction of IL-10 expression by B cells, as inhibition of STAT3 has been shown to abrogate IL-10 + B cells. 17 Taken together, the expansion of suppressive Bregs in response to inflammatory signals appears to be a mechanism that has evolved to prevent excessive inflammation and tissue damage.

In addition to inflammatory stimuli, recent studies have identified aryl hydrocarbon receptor (AhR) as an important transcription factor involved in Breg differentiation. 18, 19 Ahr has been shown to regulate the transcription of IL-10 by B cells while actively repressing the transcription of pro-inflammatory mediators. 18 In a mouse model of arthritis, the lack of Ahr expression by B cells has been demonstrated to increase Th1/Th17 responses, decrease regulatory T cells (Tregs), and lead to exacerbated arthritis as a result of impaired IL-10-producing Breg differentiation. 18 Interestingly, Blimp1, a transcription factor critical for plasma cell differentiation, 20 has also been shown to play a role in IL-10 + Breg function; as Bregs lacking Blimp-1 expression fail to efficiently suppress naïve CD4 + T cell proliferation. 21 Furthermore, evidence suggests that Bregs have the ability to differentiate into IL-10-producing plasmablasts and plasma cells in vitro and in vivo. 22, 23 Although antibody-producing plasmablasts/plasma cells are largely associated with pro-inflammatory responses, 24 a subset of IL-10 + regulatory plasmablasts have been shown to suppress immune responses while producing antibody. 25, 26 These findings suggest that B cells at any stage of development can exhibit a regulatory phenotype.

Several Breg subsets with overlapping markers and functions have been identified in mice and humans. 3 In animal models, Bregs suppress allergic airway inflammation, 27 promote tolerance in transplantation, 28, 29 and improve experimental autoimmune diseases. 22, 30, 31 Among the different subsets, IL-10-producing B cell subpopulations that constitute ~10% of circulating human B cells are the most studied in different disease settings. 3, 32 These subsets include CD1d hi CD5 + B10 Bregs, 33 CD21 + CD23 − CD24 hi marginal zone (MZ) Bregs, 34, 35 CD1d hi CD21 hi CD23 hi CD24 hi T2-MZP Bregs, 30, 36 and CD138 + CD44 hi plasmablasts. 22 In addition, T cell immunoglobulin and mucin-domain-containing protein (Tim-1) has been identified as a marker for IL-10-producing B cells in mice and is expressed by multiple Breg subsets. 37, 38 Importantly, B cell-specific Tim-1 deletion results in spontaneous multi-organ tissue inflammation, supporting a role for this Breg subset in maintaining self-tolerance and restraining tissue inflammation. 19, 38 Other Breg populations include MZ-like and MZ-progenitor B cells that express programmed cell death-ligand 1 (PD-L1) molecule in mice. 39 Immune suppression by PD-L1 hi Bregs is independent of IL-10 and mediated by the PD-1/PD-L1 pathway that can regulate follicular T-helper (Tfh) cell responses. 39 Due to the limited access to human lymphoid tissues, majority of CD38 + CD1d + IgM + CD147 + granzymeB (GzmB) + B cells, 42 and CD39 + CD73 + B cells. 43, 44 Similar to mouse models, Tim-1 + B cells that co-express IL-10 have also been reported in humans. 45 The different Breg subsets, their mechanisms of suppression, and role in different disease settings have been described in detail elsewhere, 3,4,46 and summarized here in Table 1 .

Inhibitory mechanisms of Bregs are best described by their secretion of the anti-inflammatory cytokine, IL-10. 2 Breg-derived IL-10 can convert CD4 + T cells into Tregs and type I regulatory T (Tr1) cells, 47 inhibit Th1/ Th17 differentiation, 32,48 suppress TNF-α production by monocytes, 40 and maintain the number and function of immunosuppressive invariant natural killer (iNKT) cells. 49 ,50 IL-10producing Bregs also suppress the production of IFN-α, an antiviral cytokine that is secreted by plasmacytoid dendritic cells (pDCs), 11 thereby implicating a role for Bregs in preventing hyper-inflammation and tissue damage caused by unresolved infections. Bregs also act through the secretion of other anti-inflammatory cytokines like tumor growth factor-β (TGF-β) and IL-35. Breg-derived IL-35 induces Treg expansion and inhibits Th1 and Th17 differentiation, 15, 23 whereas TGF-β induces CD8 + T cell anergy and apoptosis of effector CD4 + T cells. 51, 52 Furthermore, a subset of induced Bregs (iBregs, induced by CTLA-4 + T cells) expand Tregs in a TGF-β and indoleamine 2,3 dioxygenase (IDO)-dependent manner 53 ). Another subset of Bregs, known as Br1 cells, secrete IL-10 and allergen-specific IgG4 antibodies that regulate tolerance to allergic reactions and suppress allergen-specific T cell proliferation. 41 Additionally, a population of CD39 + CD73 + B cells suppress inflammatory reactions by inhibiting the proliferation of CD4 + and CD8 + T cells, via the production of adenosine 5′-monophosphate (5′-AMP). 43, 44 Other mechanisms of Breg immune suppression include co-stimulatory interactions with T cells, iNKT cells, and DCs that involve CD80, CD86, CD1d CTLA-4, PD-L1, and MHC class II. 4 PD-L1 hi Bregs inhibit the expansion of Tfh cells in spleen/ lymph nodes and suppress effector T cell differentiation by modulating downstream signaling pathways. 39 Figure 1 summarizes the mechanisms of suppression by Bregs.

The respiratory tract is designed with immune structures to protect the body against a wide range of potentially harmful external airborne antigens. 1,54 B cells are rarely found in the lungs of healthy humans; their presence in the lung is almost exclusively associated with lung injury, usually infection or chronic inflammation. 1 B cells are typically located within tertiary or ectopic lymphoid tissues (ELTs) in the lung, like the inducible bronchus-associated lymphoid tissue (iBALT). 1,5 Unlike well-organized secondary lymphoid organs, ELTs are loosely organized, poorly defined aggregates of lymphoid cells that develop rapidly in response to infection, chronic inflammation, or autoimmunity. 55 ELTs have separate B and T cellrich zones, Tfh cells, a network of follicular dendritic cells (FDCs), stromal mesenchymal cells, and high endothelial venules, and can vary depending on the type of pathogen or inflammatory condition that triggered their formation. 5, 55, 56 Importantly, they display localized expression of CXCL12 and CXCL13 (a strong homing signal for CXCR5 + B cells 57 ) that promote naïve B cell recruitment to the ELTs 58 ; recruited B cells then produce lymphotoxin-β that further sustain the ELT. 59, 60 Tfh cells also express CXCR5 that allows them to stay in close contact with B cells within the ELT. [61] [62] [63] Thus, ELTs contain functional germinal centers (GCs) for local B 5′-AMP, ADO Inhibits proliferation of CD4 + and CD8 + T cells 43, 44 Abbreviations 

In addition to their effector functions, B cells also produce IL-10 that limits excessive inflammation and suppresses potential proinflammatory cytokine over-production. B cell-derived IL-10 acts as an immunoregulator, inhibiting pro-inflammatory responses and preventing tissue damage resulting from exacerbated innate and adaptive immune responses. 115 Here, we focus on the role of Bregs in the immune response during respiratory infections. The role of Bregs in other infection settings has been described in detail elsewhere. 115 Respiratory viruses, such as H1N1 influenza and SARS-CoV-2 coronavirus, are a cause of severe pneumonia and acute respiratory distress syndrome (ARDS). 116 127 Another unique subset of lung-resident IL-10-producing CD19 + B220 -B cells has been shown to exacerbate Streptococcus pneumoniae infection. 128 Similarly, in fungal infections such as pneumocystis pneumonia (PCP), an increase in IL-10-producing Bregs has been associated with the inhibition of Th1/Th17 responses and effective pathogen clearance. 129 Overall, it appears that immunosuppressive functions of Bregs can be either detrimental or beneficial depending on the disease context.

Asthma is chronic inflammation of the airway characterized by heightened reactivity and sensitivity of the airway to a variety of inhaled stimuli. 130 Bregs play a protective role against hyperresponsive airway inflammation, where IL-10-producing B cells significantly suppress inflammatory reactions. 131 Functional impairments in Bregs have been associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models of disease, adoptive transfer of CD9 + Bregs suppress all asthma-related features by inhibiting effector T cells in an IL-10-dependent manner. 132 In addition, IL-10-producing CD5 + CD21 hi CD1d hi Bregs can reverse allergic airway inflammation by actively recruiting immunosuppressive Tregs to the lungs. 133 Interestingly, infection with Schistosoma mansoni worms has been shown to protect against ovalbumin-induced allergic airway inflammation by inducing IL-10-producing T2-MZP Bregs. 134 In contrast with hypersensitivity, pathology in chronic obstructive pulmonary disorder (COPD) is a result of proteolytic destruction of the extracellular lung matrix by the immune response. 135 Rituximab has shown success in the treatment of early and refractory pulmonary hemorrhage in patients with SLE, 143, 144 as well as in improving lung function in patients with RA and SSc with ILD. 145, 146 Long-term remission after B cell repopulation in rituximab-treated patients has been associated with a higher immature-to-memory B cell ratio, suggesting that repopulation of immunosuppressive CD24 hi CD38 hi Bregs might be associated with improved clinical outcomes. 147, 148 This is further supported by studies reporting an expansion of CD24 hi CD38 hi Bregs with restored STAT3 activation and IL-10 production in patients responding to rituximab therapy. 11 Further, the expansion of repopulated Bregs corresponded with normalization of pDC activation and iNKT cell function. 11, 49 However, it is important to note that not all patients respond to rituximab, 149 and to date, there is no strategy to predict which patients will respond to rituximab. One possible explanation is that an incomplete depletion of "pathogenic" B cells infiltrating the lung or/ and other tissue sites contributes to the lack of clinical response. A second possibility is that repopulating B cells in non-responding patients are being skewed toward pro-inflammatory Beffs and not suppressive Bregs by environmental milieu. Another scenario is that rituximab depletes beneficial tissue-resident Bregs that suppress inflammation, and therefore exacerbates disease. Overall, the underlying mechanisms that determine clinical response to rituximab remain to be ascertained.

The role of Bregs as negative regulators of the immune response is now well established. More recently, it has become evident that

Bregs play a role in the pathophysiology of respiratory diseases such as lung cancer, asthma, autoimmunity, and IPF. While alterations in Breg numbers and function have been identified as contributors to disease pathology, the precise role of Bregs in disease pathogenesis remains to be ascertained. There are several aspects of Breg phenotype and function that must be addressed in order to exploit their therapeutic potential.

The environmental milieu is known to play an important role in the induction of Bregs; however, specific signals in the lung microenvironment that induce Bregs remain ill-defined. In addition to TLR, BCR, and CD40 signaling, exposure to inflammatory cytokines IFN-α, IFN-β, IL-1β, IL-6, IL-21 and BAFF has been shown to enhance Breg differentiation. 2, 4 These signals are upregulated in the lung microenvironment in infections and chronic inflammatory conditions, 102, 150 suggesting their involvement in Breg induction in the airways. For instance, studies from mouse models of lung cancer suggest that Breg differentiation occurs in response to the lung tumor microenvironment. 110 The lung can experience hypoxia in pathological but sometimes also physiological situations, with associated alveolar hypoxia. 151 Moreover, cigarette smoke (CS) and CS extract activate hypoxia-inducible factor 1 (HIF-1α) in lung-epithelial cells under non-hypoxic conditions. 152 In addition to activating innate immune responses in the lung, 153 As detailed above, AhR is a key transcription factor involved in Breg differentiation. 18, 19 AhR and its ligands exhibit important immunomodulatory properties and can modulate the respiratory immune response. 155 On the one hand, AhR ligands have been shown to suppress allergic airway inflammation and prove beneficial in models of asthma. 156 On the other hand, the pathogenesis of COPD has been attributed to various cell populations expressing AhR. AhR has been shown to be a master regulator of inflammatory responses in innate immune cells and T cells, critical in driving COPD pathology. 157 The precise role of AhR in modulating respiratory disease appears to be disease and context-dependent. Further research is required to understand the multifaceted role of AhR in inflammatory lung diseases. Other signals that modulate Breg differentiation include commensal bacteria. 10 The importance of microbiota in the expansion of Bregs was confirmed by the treatment of mice with antibiotics;

antibiotic-treated mice displayed reduced Bregs in comparison with untreated mice. Improved understanding of signals driving Breg differentiation in the lung could provide new therapeutic strategies.

Another critical question is whether Bregs remain stable over time. 22 an independent study has shown that Bregs transiently secrete IL-10 and terminally differentiate into antibodysecreting cells. 158 This is further supported by studies reporting a role for plasma cell-specific transcription factor Blimp1 in the generation and function of IL-10-producing Bregs. 21 Further investigations on Breg plasticity and stability are necessary to understand the possibility of generating a prolonged Breg phenotype.

Current therapies for various respiratory diseases focus on disease management rather than offer a cure and become toxic and ineffective over a period of time. Highly targeted immunotherapies offer several advantages over conventional steroid and immunosuppressants and have proven highly effective in the treatment of pulmonary diseases. 159, 160 The use of rituximab for the treatment of pulmonary manifestations in autoimmune diseases has shown some success. [143] [144] [145] [146] While targeting aberrant B cells is beneficial, the lack of clinical response in some patients could be associated with the depletion of immunosuppressive Bregs. Therapies targeting specific subsets of Bregs could be advantageous in different disease settings. For instance, increased infiltration of PD-L1 hi Bregs in lung tumors has provided the rationale for PD-L1 and PD-1 blockade. 161 Remarkably, studies show that targeting the PD-1/PD-L1 pathway can improve the survival of patients with advanced lung cancer. 162 Several strategies to isolate, expand, or deplete Bregs to treat various immune-related pathologies have been discussed elsewhere. 4 Taken together, these reports suggest that a better understanding of lung-infiltrating Bregs could provide novel therapeutic targets for improved management of various respiratory diseases. 

We thank PA Blair and EC Rosser for her comments on the manuscript. HA Shuwa is funded by Petroleum Technology Development Fund (SHS/1327/18).

There is no conflict of interest to declare.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

https://orcid.org/0000-0003-2516-9438

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