The immune potential and immunopathology of cytokine-producing B cell subsets: A comprehensive review

Abstract

B lymphocytes are generally recognized for their potential to mediate humoral immunity by producing different antibody isotypes and being involved in opsonization and complement fixation. Nevertheless, the non-classical, antibody-independent immune potential of B cell subsets has attracted much attention especially in the past decade. These B cells can release a broad variety of cytokines (such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-α, IFN-γ, TNF-α, TGF-β, LT), and can be classified into distinct subsets depending on the particular cytokine profile, thus emerging the concept of cytokine-producing B cell subsets. Although there is still controversy surrounding the key cell surface markers, intracellular factors and cellular origins of cytokine-producing B cell subsets, accumulating evidence indicates that these B cells are endowed with great potential to regulate both innate and adaptive arms of immune system though releasing cytokines. On the one hand, they promote immune responses through mounting Th1/Th2/Th17 and neutrophil response, inducing DC maturation and formation of lymphoid structures, increasing NK cell and macrophage activation, enhancing development of themselves and sustaining antibody production. On the other hand, they can negatively regulate immune responses by suppressing Th cell responses, inhibiting Tr1 cell and Foxp3⁺ Treg differentiation, impairing APC function and pro-inflammatory cytokine release by monocytes, and inducing CD8⁺ T cell anergy and CD4⁺ T cell apoptosis. Therefore, cytokine-producing B cell subsets have multifunctional functions in health and diseases, playing pathologic as well as protective roles in autoimmunity, infection, allergy, and even malignancy. In this review, we revisit the history of discovering cytokine-producing B cells, describe the identification of cytokine-producing B cell subsets, introduce the origins of cytokine-producing B cell subsets as well as molecular and cellular mechanisms for their differentiation, and summarize the recent progress made toward understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders.

Introduction

B lymphocytes, a unique cell type in the immune system, have been generally characterized by their ability to differentiate into antibody-producing plasma cells. Therefore, their dominant role in humoral immunity has long been considered as the primary, unique function of B cells. B cells are traditionally divided into three subsets: B-1 B cells, follicular (FO) B cells, and marginal zone (MZ) B cells [1], [2], [3]. The development of each subset is tightly regulated by a network of stimuli and by their microenvironment, and they vary in location, surface markers, function, and manner of activation [2], [3], [4]. B-1 B cells are phenotypically classified as CD5^+/−CD43⁺CD11b⁺IL-5R⁺ B cells and seed the peritoneal and pleural cavities. They can be activated by many stimuli, including antigens, lipopolysaccharide (LPS), and cytokines (IL-5, IL-10), and are associated with the production of natural antibodies; moreover, they can function to bridge innate and adaptive immunity under certain microenvironmental conditions [5], [6], [7], [8]. CD24⁺CD21⁺B220⁺ FO B cells are activated in the follicular niche by T-dependent (TD) antigen signals mediated by the B cell receptor (BCR), CD40, and Toll-like receptors (TLRs). Aside from their antigen-presenting functions, activated FO B cells differentiate into short-lived plasma cells in the periphery [9], [10], [11]. In contrast, CD1d^hiCD21^hi MZ B cells can be stimulated with T-independent (TI) antigens and can differentiate into short-lived plasma cells that exert innate-like function, even without BCR signals [4]. Therefore, it had been believed for a long time that all B cell functions can be explained by antibody-dependent mechanisms.

In addition to the antibody-dependent classical function of B cells, more and more basic and clinic evidence indicates B cells may amplify or suppress immune responses in an antibody-independent manner, for example, clinical findings within the last two decades show that B cell depletion by rituximab (a humanized anti-CD20 antibody) apparently leads to the remission of autoimmune diseases without a concurrent reduction in serum autoantibody levels [12], [13]. Lund and Harris first raised the concept of effector B cell subsets, which are characterized by their unique cytokine profiles and opposing effects on polarizing T helper (Th) cells during their differentiation, as follows [14]: Be1 cells produce interferon (IFN)-γ, IL-12p40, tumor necrosis factor (TNF)-α, and IL-10, whereas Be2 produce IL-2, IL-4, IL-6, IL-13, IL-10, and TNF-α [14]. Since then, more attention has been paid to studying cytokine-producing B cell subsets, and advances in understanding their unique function have been achieved in the past decade. A growing body of cytokine-producing B cell subsets have been identified in physiological and pathological conditions, such as IL-10-producing CD1d^hiCD5⁺ B10 B cells, IL-17-producing B cells, lymphotoxin (LT)-producing B cells, IFN-α-producing PDCA-1⁺Siglec-H⁻ B cells, and IFN-γ-producing CD11a^hiFcγRIII^hi innate B cells, among others [15], [16], [17], [18], [19]. The cytokines produced by these B cell subsets are associated with both pathogenic and protective roles in various immunological disorders [15], [16], [17], [20], [21]. Here, we revisit the history of discovering cytokine-producing B cells; describe the identification of cytokine-producing B cell subsets; discuss the origins of cytokine-producing B cell subsets, and the roles of T cells, dendritic cells (DCs), and macrophage-derived factors in regulating their differentiation; Also, we summarize the recent progress made in understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders.