Introduction: Regulatory B Cell Special Issue—making all the pieces fit

B cells positively regulate immune responses and inflammation through antibody production and antigen presentation for optimal CD4+ T-cell activation (1). However, specific and functionally important B-cell subsets with negative regulatory properties have been recently identified that contribute to immunological tolerance by down-modulating immune responses under homeostatic, as well as inflammatory and pathogenic, conditions. This Special Issue focuses on regulatory B-cell subsets that suppress disease symptoms in experimental autoimmune encephalitis (EAE), chronic colitis, contact hypersensitivity [delayed type hypersensitivity (DTH)], collagen-induced arthritis, allergy, infection, lupus and non-obese diabetic mouse models, and other B-cell subsets that augment acute and chronic inflammation. Despite their short tenure on the immunology stage, regulatory B cells have garnered considerable attention as important components of the cellular network that modulates the immune system. The concept of regulatory B cells first appeared in the literature before the identification of phenotypically distinct B-cell subsets. B-cell suppression of immune activation was first identified during DTH responses in guinea pigs in 1974 (2, 3). These studies introduced the concept that ‘suppressor B cells’ could regulate T-cell function, but this notion and the parallel belief in ‘suppressor T cells’ eventually fell from favor. However, Wolf et al. re-established this concept when they demonstrated in 1996 that the disease course of EAE was prolonged in B-cell-deficient mice (4). Mizoguchi et al. subsequently demonstrated a suppressive role for B cells in chronic colitis in 1997 and were the first to publish the term ‘regulatory B cells’ in 2002 to designate B cells that regulate immune responses by secreting IL-10 (5, 6). These studies were accompanied by numerous provocative papers from 2000 to 2008 that demonstrated B-cell regulatory effects on diverse autoimmune responses (7–17). These and other papers at the time documented the existence of regulatory B cells and repeatedly observed that IL-10 was central to their regulatory function. Despite this, the phenotype, functions and molecular characteristics of regulatory B cells have remained complicated and are becoming even more diverse. In large part, uncertainty within the regulatory B-cell field reflects an evolution of knowledge inherent to cutting-edge basic biomedical research. Diverse laboratories approaching the same issue from different perspectives commonly generate confusion within the literature early in the discovery process until observations are sufficiently validated and enough knowledge is gained to fit the puzzle pieces together. This pattern of scientific evolution was clearly displayed when the biology of regulatory T cells first came into focus, and remnants of uncertainty remain. Even now, our current appreciation of the functional diversity within the B-cell lineage is likely to be naive. Nonetheless, the chapters within this Special Issue on regulatory B cells collectively highlight the fact that B cells are functionally diverse as a population, as is now appreciated for T-cell subsets. Heterogeneity of the B-cell antigen receptor (BCR) and cell surface receptors unquestionably contributes to the observed functional diversity among B-cell populations. The current literature also suggests that B cells have the capacity to produce a variety of cytokines and inflammatory mediators, including IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, IL-17, IL-33, IL-35, GM-CSF, IFN-γ and TNF, but the extent to which these are expressed by individual or overlapping B cells needs to be determined. Further studies are also needed to document the reality of this diversity, as contaminating cells within B-cellenriched populations may have contributed transcripts/ proteins in some cases, and the natural expression of other cytokines has been difficult to establish in any cell population. Thus, future studies are needed to validate one-off observations, findings from single laboratories, and to better understand those observations that are consistent across numerous groups in order to yield a more complete picture of how variably defined B-cell subsets regulate immune responses. In an effort to illustrate the current state of the regulatory B-cell field, nine groups of investigators have collaborated to generate this issue by providing their independent perspectives on specific topics within the field. This Special Issue also illustrates the reality that the term ‘regulatory B cell’ as it is currently used in the literature is likely to circumscribe a wide collection of functionally distinct B-cell subsets with potent regulatory effects. For example, although IL-10 production is commonly associated with ‘regulatory B cells’ and is frequently assumed to be their mechanism of negative regulation, some groups have identified populations of B cells with IL-10-independent regulatory functions. As no specific phenotypic markers, signaling molecules or transcription factors have been identified to delineate among regulatory B-cell subsets, the functionally important cytokines or cell surface molecules that drive their regulatory function currently offer the best means to identify specific B-cell subsets with different functional properties (18). Thus, regulatory cells do not appear to represent specific lineages within the B-cell population but may delimit B cells that have acquired distinct functional abilities in response to their environmental cues. Received 31 July 2015, accepted International Immunology, Vol. 27, No. 10, pp. 467–470 doi:10.1093/intimm/dxv047