The number of regulatory B cell “followers” has increased steadily in the last few years confirming the rising interest in understanding the relevance of this subset of B cells in controlling immune responses in a variety of immune‐related diseases. Regulatory B cells (Breg) are potent modulators of immune responses, which prevent excessive inflammation and maintain immune homeostasis after infection or tissue‐injury.¹ Abnormalities in Breg number and function have been identified in immune‐related pathologies such as autoimmune disease, chronic infections, cancer, and in the rejection of transplants.^{1, 2} Thus, it is of utmost clinical importance to understand the ontogeny of these populations, to phenotypically characterize Breg populations, and to understand the cellular signals and the molecular “cues,” which drive Breg differentiation. By better characterizing Breg populations and the processes leading to their differentiation, we can identify target molecules/pathways for therapeutic interventions in immune‐related pathologies.

The first manuscript describing the existence of B cells with suppressive function dates back to the 1970’s, where the suppressive function of B cells was first described in studies examining delayed‐type hypersensitivity (DTH) reactions using either 2,4 dinitrofluorobenzene (DNFB) or ovalbumin (OVA) in incomplete Freund's adjuvant (IFA) or paraeminobenzoic acid‐Hen egg albumin conjugate (PABA‐HEA) in guinea pigs. Increased intensity and prolonged DTH reactions were observed in B cell‐depleted DNFB‐sensitized guinea pigs.³ Later studies showed that adoptive transfer of lymphocytes or total splenocytes suppressed the intensity of the DTH response.^{4, 5} These cells were dubbed “suppressor B cells.” However, the mechanisms behind the suppressive response were never investigated and the study of B cell regulation was not renewed until the 1990’s, when the late Charles Janeway and his team observed that B cell‐deficient mice developed an exacerbated form of experimental autoimmune encephalomyelitis (EAE).⁶ It was not until 10 years later that almost simultaneously three papers revisited the concept of B cells as suppressors of immune responses in different autoimmune diseases and the term regulatory B cells was coined.^7-9

Nevertheless, the field remained stalled for several years until B cell‐depletion therapies were trialed and proved efficacious in rheumatic diseases. B cell therapy (BCT) originates from the cancer field where B cell‐depletion therapies are used in the clinic to remove B cells in hematological B cell malignancies.¹⁰ A pioneering study conducted at University College, London, back in the early 2000’s, confirmed the efficacy that rituximab had in ameliorating disease in a small number of patients with refractory rheumatoid arthritis (RA).¹¹ This initial study was followed by several clinical trials showing the therapeutic efficacy of this treatment in rheumatoid arthritis, systemic lupus erythematosus, and more recently in multiple sclerosis (MS).^12-14 The majority of studies that have been focusing on understanding how B cell depletion therapies work showed, somewhat surprisingly, that autoantibodies known to play an important part in the pathogenesis of these diseases remain largely unaltered after B cell depletion. These results reignited an interest in understanding how B cells contribute to the pathogenesis of immune responses through antibody‐independent mechanisms including antigen processing cells and cytokine/chemokine production.

Twenty years later, we thought that it was timely to dedicate an entire volume to this underappreciated B cell subset, which regulates many of the immune responses in the body. In this volume, experts in this field discuss and reconcile issues related to the identification of Bregs, including whether Bregs are lineage‐specific or if they arise at any stage of maturation in response to microenvironmental “cues”; the importance of tissue location and tissue‐associated pathology in their differentiation; the need of interaction with other immune cells and how other immune cells shape Breg function and differentiation (Figure 1).

Regulatory B cells (Bregs) play an important role in the control of inflammation, and IL‐10 production is considered to be the hallmark for their identification. The identification of a universal surface marker, which captures the cellular and functional heterogeneity of human and murine Breg subsets, has so far evaded discovery.^{1, 15} In particular, we all know in the field that when we study Bregs by flow cytometry, for example, we are confronted with a highly heterogeneous cell population and that different B cell subsets, regardless of its developmental stage, can in response to an appropriate signal, become suppressive. Ma et al¹⁶ provide an phenotypical and functional overview of the different subsets of Bregs that have been so far reported. In particular, the authors describe how Bregs with different phenotypes arise in different allergic conditions including in food allergy and atopic dermatitis. They show that whereas CD9‐expressing Bregs play a preventive role in both mouse models and patients with allergic asthma,^{17, 18} CD5‐expressing and TGFβ‐producing Bregs have been implicated in controlling food allergy and atopic dermatitis.¹⁹ They also touch upon how Breg responses change according to different stimuli and according to tissue residency, thus justifying the importance of gaining increased insight in this field, in order to develop more targeted therapies to allergic disease. An example of the clinical utility of harnessing Bregs for the treatment of allergies is allergen‐specific immunotherapy. Beekeepers tolerized to bee venom allergen phospholipase A2, have increased frequencies of IL‐10⁺IgG4⁺CD25^hiCD71^hiCD73^‐ Bregs (BR1) compared to healthy controls. Remarkably, allergic patients have increased numbers of BR1 cells after receiving specific immunotherapy, thus linking BR1 cells to the maintenance of tolerance against bee venom allergens.²⁰

Cherukuri et al²¹ also proposed TIM‐1 as a shared surface marker for Breg subsets from murine models of transplantation. They explore in detail its unique role in promoting the upregulation of IL‐10 and other inhibitory cytokines and receptors previously ascribed to Breg function, as well as the mechanisms implemented by Bregs to improve allograft survival. This group also points to the persistent challenge remaining in the identification of a universal human Breg marker, as only around 5% of peripheral blood B cells express TIM‐1.¹⁶ Despite a continuous lack of a unifying markers, mechanistic and translational progress have been made. Rothstein and colleagues have reported recently encouraging findings on the clinical utility of using the IL‐10/TNF (Breg:B effector) ratio as a biomarker for the prediction of clinical outcomes in patients undergoing transplantation; patients with allograft rejection had decreased numbers of IL‐10⁺Bregs.²¹ The authors also provide interesting insight into the effects of immunosuppressive agents on Breg function and the current conundrum faced in the immune‐suppressive field; that is how can we promote Breg function, while depleting pathogenic B cells? Further elucidation of the molecular signals required for Breg differentiation and the identification of unique surface receptors would help us to address this question.

Multiple sclerosis (MS) has been historically considered a T cell‐driven disease; however, the recent undeniable success of B cell‐depletion therapy in the amelioration of MS clearly shows the involvement of B cells in the pathology of this disease.^{22, 23} Wang et al²⁴ provide a balanced resume of recent findings showing the complex interplay of both pathogenic and protective effects that B cells have in this disease.

The first evidence of a protective role of IL‐10 producing B cells in neuroinflammation was first described in the EAE model.⁸ Since this initial study, multiple regulatory roles and functions of regulatory plasmablasts (PB) and plasma cells (PC) have been documented in EAE.^{25, 26} Wang et al nicely tie old findings with their latest discovery showing that the gut microbiota, known to shape immune responses, can promote the differentiation of regulatory IgA⁺ plasma cells. They also provide a “theoretical platform” discussing the potential that these cells have in the regulation of neuroinflammation and if and how regulatory PCs, that remain post‐rituximab therapy, contribute to MS amelioration. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next‐generation B cell‐directed therapies for the treatment of MS.

The role played by B cells in different tissues/organs is still under‐investigation. B cells are key sentinels at the mucosal sites and contribute to local immune responses through the release of antibodies and cytokines and through the presentation of antigen. Menon et al²⁷ provide a detailed overview of the current state‐of‐knowledge on the role of B cells and Bregs in the mucosa‐associated lymphoid tissue (MALT) in the lung in the healthy state and in immune‐related lung pathologies. B cells are sparsely present in healthy lung tissue but arise as a result of infection or chronic inflammation and are predominantly found in ectopic lymphoid tissues (ELT).²⁸ Importantly, B cells can have proinflammatory and anti‐inflammatory roles, dependent on the microenvironmental cues these cells receive and abnormalities in Breg numbers and/or function are well‐documented in various lung pathologies. Topically, the authors highlight recent research into the role of Bregs in severe Sars‐Cov2 infection, where decreased numbers of IL‐10⁺Bregs have been suggested to contribute to increased immunopathology.^{27, 29}

Immune evasion by tumor cells is a major problem in the design of therapeutics and in the successful treatment of solid cancers.³⁰ It is well‐established that regulatory T cells promote an immunotolerant environment, which contributes to immune evasion.³⁰ However, compared to autoimmunity, where it is well‐established that they are numerically deficient and functionally impaired,² the contribution of Bregs in solid tumors is in its infancy. Mounting evidence increasingly show that Bregs play a role in immune evasion in cancer and increased numbers of Bregs can be found intra‐tumor in multiple mouse models of cancer.³¹ Menon et al report findings showing that increased number of tumor‐infiltrating IL‐10⁺Breg, suppressing tumoricidal responses, are found in the lungs of cancer patients.^{32, 33}

Michaud et al³¹ describe the pro and anti‐tumorigenic role that regulatory B cell and B cell play respectively in the anti‐tumor microenvironment. They minutely review the existing literature showing how B cells recruited in tumors take advantage of their functional armory to increase cytotoxity and the killing of the tumor‐target. B cells contribute to the clearance of tumors via production of antibody‐dependent cellular cytotoxicity (ADCC) facilitating phagocytosis by dendritic cells; by enhancing presentation of tumors antigens to T cells; and via the production of proinflammatory cytokines.^34-36 On the other hand, Bregs via the production of IL‐35 and IL‐10 contribute to the enhancement of the already immune‐tolerogenic environment present in tumors. Michaud and colleagues propose how Bregs could be exploited in cancer treatment, and how, for example, selectively targeting IL‐35‐expressing Bregs could increase efficacy of cancer immunotherapy.

Bregs require a direct interaction with other immune cells to exert their suppressive function. Bregs interact with CD4⁺ T cells and inhibit their differentiation into Th1 and Th17 cells, while promoting the development of FoxP3⁺Tregs. Bregs also suppress IL‐12 producing dendritic cells, TNFα producing monocytes, and cytotoxic CD8⁺ T cells.¹ The most recently discovered cell type found to cross‐talk with Bregs are invariant natural killer T cells (iNKT)^{37, 38}; a subset of cells bridging innate and adaptive responses to pathogens while also providing key regulation of immune homeostasis.³⁹ Leadbetter and Karlsson provide a thorough review covering several aspects of iNKT and B cell interaction and how the outcome of this encounter leads to the generation of iNKT regulatory cell (iNKT_reg)¹⁵ or iNKT follicular helper (iNKT_FH) cells, that in turn support pathogen‐specific effector B cell differentiation.⁴⁰

In addition, an extensive review of the role that iNKT‐B cell interactions have in modulating several autoimmune diseases and in cancer is presented. iNKT cells provide cognate help to B cells, which helps to promote the generation of tumor‐specific antibodies.⁴¹ Conversely, the downregulation of CD1d in B cell leukemia contributes to immune evasion of the lytic function of iNKT cells.^42-44 Whether iNKT cells can induce Bregs in the context of cancer remains to be determined. Targeted therapies increasing CD1d expression on B cells could be used to increase the tumoricidal activity of iNKT cells. Examining the nature of the antigen presented by CD1d as well as the tissue location of B cell:iNKT cell interactions could also be exploited for therapy.

The formation of antigen‐specific B cell clones and the incremental increase in antigen receptor affinity for any given antigen are key process for the formation of humoral immunity against viral pathogens. In this review, Burton and Maini, using the example of hepatitis B core antigen (HBcAg) and surface antigen (HBsAg), outline how the antigen load and properties of the antigen lead to the formation of memory and describe what determines whether a B cell clone proceeds through the germinal center (GC) reaction or through the extrafollicular differentiation pathway.⁴⁵ Chronic hepatitis B infection is characterized by a persistent antigen load and an exhaustion of virus‐specific CD8⁺ T cells. The authors delve into the dysregulation of the GC reaction in chronic hepatitis B patients and the preference of B cell clones to enter the extrafollicular B cell pathway, as is evidenced by the lack of long‐lived plasma cell and memory B cell formation. Key to this cell fate decision are prefollicular helper T cells. The authors elucidate the mechanism behind chronic viral infection and the impact this has on the skewing of CD4 T cells subsets away from an archetypical T follicular helper cell phenotype, thereby facilitating the generation of extrafollicular B cell responses. Lastly, the authors touch on ectopic germinal center formation and their role in forming intrahepatic atypical memory B cell responses in hepatitis B patients.

Taken together, these articles will provide an extensive overview of how B cells beyond antibodies can control immune responses to autoantigens but also to viral infections and cancer. This issue also provides several insights into the mechanisms of action of B cell depletion and how novel therapies targeting the interaction between B cells and cells of the innate immune system are currently used to inform drug development. By better understanding the phenotype, ontogeny, and molecular pathways leading to Breg differentiation, researchers can overcome the caveats of broad‐spectrum B cell depletion and take more targeted approaches for the development of therapeutics specifically depleting pathogenic B cells and leaving regulatory B cells intact.

在过去几年中，调节性 B 细胞“追随者”的数量稳步增加，这证实了人们对了解该 B 细胞亚群在控制各种免疫相关疾病的免疫反应中的相关性的兴趣日益增加。调节性 B 细胞 (Breg) 是免疫反应的有效调节剂，可防止过度炎症并在感染或组织损伤后维持免疫稳态。¹ Breg 数量和功能异常已在免疫相关病理学中被发现，例如自身免疫疾病、慢性感染、癌症和移植排斥。^1、2因此，了解这些群体的个体发育、表征 Breg 群体的表型以及了解驱动 Breg 分化的细胞信号和分子“线索”具有极其重要的临床意义。通过更好地表征 Breg 种群和导致它们分化的过程，我们可以确定用于免疫相关病理学治疗干预的目标分子/途径。

第一份描述具有抑制功能的 B 细胞存在的手稿可以追溯到 1970 年代，其中 B 细胞的抑制功能首次在使用 2,4 二硝基氟苯 (DNFB) 或卵清蛋白检查迟发型超敏反应 (DTH) 反应的研究中描述（OVA）在豚鼠的不完全弗氏佐剂（IFA）或对氨基苯甲酸-鸡蛋清蛋白缀合物（PABA-HEA）中。在 B 细胞耗尽的 DNFB 致敏豚鼠中观察到强度增加和 DTH 反应延长。³后来的研究表明，淋巴细胞或总脾细胞的过继转移抑制了 DTH 反应的强度。^4、5这些细胞被称为“抑制性 B 细胞”。然而，抑制反应背后的机制从未被研究过，直到 1990 年代，已故的 Charles Janeway 和他的团队观察到 B 细胞缺陷的小鼠发展出一种加剧的实验性自身免疫性脑脊髓炎（EAE），B 细胞调节的研究才重新开始。 ）。⁶直到 10 年后，几乎同时三篇论文重新审视了 B 细胞作为不同自身免疫疾病中免疫反应抑制因子的概念，并创造了术语调节性 B 细胞。^7-9

尽管如此，该领域仍然停滞了几年，直到 B 细胞耗竭疗法被试验并证明对风湿病有效。B 细胞疗法 (BCT) 起源于癌症领域，临床上使用 B 细胞耗竭疗法去除血液学 B 细胞恶性肿瘤中的 B 细胞。¹⁰早在 2000 年代初期，在伦敦大学学院进行的一项开创性研究证实了利妥昔单抗在改善少数难治性类风湿性关节炎 (RA) 患者的疾病方面的功效。^{11 在}这项初步研究之后，几项临床试验显示了这种疗法对类风湿性关节炎、系统性红斑狼疮以及最近在多发性硬化症 (MS) 中的疗效。^12-14大多数专注于了解 B 细胞耗竭疗法如何工作的研究表明，在 B 细胞耗竭后，已知在这些疾病的发病机制中起重要作用的自身抗体在很大程度上保持不变，这有点令人惊讶。这些结果重新点燃了人们对了解 B 细胞如何通过不依赖抗体的机制（包括抗原加工细胞和细胞因子/趋化因子产生）促进免疫反应发病机制的兴趣。

二十年后，我们认为是时候将一整本书专用于这个被低估的 B 细胞亚群，它调节体内的许多免疫反应。在本卷中，该领域的专家讨论并协调了与 Bregs 识别相关的问题，包括 Bregs 是否具有谱系特异性，或者它们是否在成熟的任何阶段出现，以响应微环境“线索”；组织定位和组织相关病理学在其分化中的重要性；与其他免疫细胞相互作用的需要以及其他免疫细胞如何塑造 Breg 功能和分化（图 1）。

调节性 B 细胞 (Bregs) 在控制炎症方面发挥着重要作用，IL-10 的产生被认为是识别它们的标志。迄今为止，通用表面标记物的鉴定可捕获人类和鼠类 Breg 亚群的细胞和功能异质性，但尚未被发现。^{1, 15}特别是，我们在该领域都知道，例如，当我们通过流式细胞术研究 Bregs 时，我们面临着高度异质性的细胞群，并且不同的 B 细胞亚群，无论其发育阶段如何，都可以对一个适当的信号，变得抑制。马等人¹⁶提供迄今为止已报道的不同 Bregs 子集的表型和功能概述。特别是，作者描述了具有不同表型的 Bregs 如何在不同的过敏条件下出现，包括食物过敏和特应性皮炎。他们表明，虽然表达 CD9 的 Bregs 在小鼠模型和过敏性哮喘患者中都起到预防作用，但^{17, 18}个表达 CD5 和产生 TGFβ 的 Bregs 与控制食物过敏和特应性皮炎有关。¹⁹他们还谈到了 Breg 反应如何根据不同的刺激和组织驻留而变化，从而证明了在该领域获得更多洞察力的重要性，以便开发针对过敏性疾病的更有针对性的疗法。利用 Bregs 治疗过敏症的临床效用的一个例子是过敏原特异性免疫疗法。养蜂人对蜂毒过敏原磷脂酶 A2 耐受，IL-10 ⁺ IgG4 ⁺ CD25 ^hi CD71 ^hi CD73频率增加^-Bregs (BR1) 与健康对照相比。值得注意的是，过敏患者在接受特异性免疫治疗后 BR1 细胞数量增加，从而将 BR1 细胞与维持对蜂毒过敏原的耐受性联系起来。²⁰

Cherukuri 等人²¹还提出 TIM-1 作为来自移植小鼠模型的 Breg 亚群的共享表面标记。他们详细探讨了其在促进 IL-10 和其他抑制性细胞因子和受体上调方面的独特作用，这些细胞因子和受体以前归因于 Breg 功能，以及 Bregs 实施的提高同种异体移植物存活率的机制。该小组还指出，在鉴定通用人类 Breg 标记物方面仍存在持续挑战，因为只有约 5% 的外周血 B 细胞表达 TIM-1。¹⁶尽管一直缺乏统一的标记，但在机制和转化方面取得了进展。Rothstein 及其同事最近报告了关于使用 IL-10/TNF（Breg：B 效应子）比率作为预测接受移植患者临床结果的生物标志物的临床效用的令人鼓舞的发现；同种异体移植排斥患者的 IL-10 ⁺ Bregs数量减少。²¹作者还对免疫抑制剂对 Breg 功能的影响以及当前免疫抑制领域面临的难题提供了有趣的见解；那就是我们如何在消耗致病性 B 细胞的同时促进 Breg 功能？进一步阐明 Breg 分化所需的分子信号和独特表面受体的鉴定将有助于我们解决这个问题。

多发性硬化症 (MS) 历来被认为是 T 细胞驱动的疾病；然而，最近不可否认的 B 细胞耗竭疗法在改善 MS 方面取得了不可否认的成功，这清楚地表明 B 细胞参与了该疾病的病理学。^{22, 23} Wang 等人²⁴对最近的发现进行了平衡的总结，这些发现表明 B 细胞在这种疾病中的致病和保护作用之间存在复杂的相互作用。

在 EAE 模型中首次描述了产生 IL-10 的 B 细胞在神经炎症中的保护作用的第一个证据。⁸自这项初步研究以来，已在 EAE 中记录了调节性浆母细胞 (PB) 和浆细胞 (PC) 的多种调节作用和功能。^{25, 26} Wang 等人将旧发现与他们的最新发现很好地结合起来，表明肠道微生物群，已知塑造免疫反应，可以促进调节性 IgA ⁺浆细胞。他们还提供了一个“理论平台”，讨论这些细胞在调节神经炎症方面的潜力，以及在利妥昔单抗治疗后仍然存在的调节性 PC 是否以及如何有助于 MS 的改善。更好地了解不同 B 细胞亚群对神经炎症调节的贡献，以及影响这些亚群发展、维持和迁移的因素，对于合理化用于治疗 MS 的下一代 B 细胞定向疗法非常重要.

B细胞在不同组织/器官中的作用仍在研究中。B 细胞是粘膜部位的关键哨兵，通过抗体和细胞因子的释放以及抗原的呈递促进局部免疫反应。Menon 等人²⁷详细概述了 B 细胞和 Bregs 在健康状态下肺部粘膜相关淋巴组织 (MALT) 和免疫相关肺部病理学中的作用的当前知识状态。B 细胞很少存在于健康的肺组织中，但由于感染或慢性炎症而出现，主要存在于异位淋巴组织 (ELT) 中。²⁸重要的是，B 细胞可以具有促炎和抗炎作用，这取决于这些细胞接受的微环境线索，并且 Breg 数量和/或功能的异常在各种肺部病理中都有充分的记录。作者重点强调了最近关于 Bregs 在严重 Sars-Cov2 感染中的作用的研究，其中 IL-10 ⁺ Bregs 的数量减少被认为有助于增加免疫病理学。^27、29

肿瘤细胞的免疫逃避是治疗设计和实体癌成功治疗中的一个主要问题。³⁰众所周知，调节性 T 细胞促进免疫耐受环境，这有助于逃避免疫。³⁰然而，与自身免疫相比，自身免疫在数量上和功能上都存在缺陷²，Bregs 在实体瘤中的作用还处于起步阶段。越来越多的证据表明，Bregs 在癌症的免疫逃避中发挥作用，并且在多种癌症小鼠模型的肿瘤内可以发现数量增加的 Bregs。³¹ Menon 等人报告的研究结果表明，肿瘤浸润性 IL-10 ⁺在癌症患者的肺部发现了抑制肿瘤反应的 Breg。^{32, 33}

Michaud 等人³¹描述了调节性 B 细胞和 B 细胞分别在抗肿瘤微环境中发挥的促肿瘤作用和抗肿瘤作用。他们仔细回顾了现有文献，这些文献显示了在肿瘤中募集的 B 细胞如何利用其功能性武器来增加细胞毒性和杀死肿瘤靶点。B 细胞通过产生抗体依赖性细胞毒性 (ADCC) 促进树突状细胞的吞噬作用来清除肿瘤；通过增强肿瘤抗原向 T 细胞的呈递；并通过促炎细胞因子的产生。^34-36另一方面，Bregs 通过产生 IL-35 和 IL-10 有助于增强肿瘤中已经存在的免疫耐受环境。Michaud 及其同事提出了如何在癌症治疗中利用 Bregs，以及例如如何选择性地靶向表达 IL-35 的 Bregs 可以提高癌症免疫疗法的疗效。

Bregs 需要与其他免疫细胞直接相互作用才能发挥其抑制功能。Bregs 与 CD4 ⁺ T 细胞相互作用并抑制其分化为 Th1 和 Th17 细胞，同时促进 FoxP3 ⁺ Tregs的发育。Bregs 还抑制产生 IL-12 的树突细胞、产生 TNFα 的单核细胞和细胞毒性 CD8 ⁺ T 细胞。¹最近发现的与 Bregs 发生串扰的细胞类型是不变的自然杀伤 T 细胞 (iNKT) ^{37, 38}；桥接对病原体的先天和适应性反应的细胞亚群，同时还提供免疫稳态的关键调节。³⁹Leadbetter 和 Karlsson 对 iNKT 和 B 细胞相互作用的几个方面进行了全面审查，以及这种相遇的结果如何导致产生 iNKT 调节细胞 (iNKT _reg ) ¹⁵或 iNKT 滤泡辅助 (iNKT _FH ) 细胞，进而支持病原体特异性效应 B 细胞分化。⁴⁰

此外，还对 iNKT-B 细胞相互作用在调节多种自身免疫疾病和癌症中的作用进行了广泛的回顾。iNKT 细胞为 B 细胞提供同源帮助，有助于促进肿瘤特异性抗体的产生。⁴¹相反，B 细胞白血病中 CD1d 的下调有助于免疫逃避 iNKT 细胞的裂解功能。^42-44 iNKT 细胞是否可以在癌症背景下诱导 Bregs 仍有待确定。增加 B 细胞上 CD1d 表达的靶向治疗可用于增加 iNKT 细胞的肿瘤活性。检查 CD1d 呈递的抗原的性质以及 B 细胞的组织位置：iNKT 细胞相互作用也可用于治疗。

抗原特异性 B 细胞克隆的形成和抗原受体对任何给定抗原的亲和力逐渐增加是形成针对病毒病原体的体液免疫的关键过程。在这篇综述中，Burton 和 Maini 以乙型肝炎核心抗原 (HBcAg) 和表面抗原 (HBsAg) 为例，概述了抗原负载和抗原特性如何导致记忆的形成，并描述了是什么决定了 B 细胞是否克隆通过生发中心 (GC) 反应或通过滤泡外分化途径进行。⁴⁵慢性乙型肝炎感染的特点是持续的抗原负荷和病毒特异性 CD8 ⁺T细胞。作者深入研究了慢性乙型肝炎患者 GC 反应的失调以及 B 细胞克隆倾向于进入滤泡外 B 细胞途径，这可以通过缺乏长寿命浆细胞和记忆 B 细胞形成来证明。这种细胞命运决定的关键是前滤泡辅助 T 细胞。作者阐明了慢性病毒感染背后的机制及其对 CD4 T 细胞亚群偏离原型 T 滤泡辅助细胞表型的影响，从而促进了滤泡外 B 细胞反应的产生。最后，作者谈到了异位生发中心的形成及其在乙型肝炎患者肝内非典型记忆 B 细胞反应中的作用。

综上所述，这些文章将广泛概述除抗体之外的 B 细胞如何控制对自身抗原以及病毒感染和癌症的免疫反应。本期还提供了一些关于 B 细胞耗竭作用机制的见解，以及目前如何使用针对 B 细胞与先天免疫系统细胞之间相互作用的新疗法来为药物开发提供信息。通过更好地了解导致 Breg 分化的表型、个体发育和分子途径，研究人员可以克服广谱 B 细胞耗竭的警告，并采取更有针对性的方法来开发治疗方法，特别是耗竭致病性 B 细胞并保持调节性 B 细胞完整。