Why do human B cells secrete granzyme B? Insights into a novel B-cell differentiation pathway

Abstract

B cells are generally believed to operate as producers of high affinity antibodies to defend the body against microorganisms, whereas cellular cytotoxicity is considered as an exclusive prerogative of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In conflict with this dogma, recent studies have demonstrated that the combination of interleukin-21 (IL-21) and B-cell receptor (BCR) stimulation enables B cells to produce and secrete the active form of the cytotoxic serine protease granzyme B (GrB). Although the production of GrB by B cells is not accompanied by that of perforin as in the case of many other GrB-secreting cells, recent findings suggest GrB secretion by B cells may play a significant role in early antiviral immune responses, in the regulation of autoimmune responses, and in cancer immunosurveillance. Here, we discuss in detail how GrB-secreting B cells may influence a variety of immune processes. A better understanding of the role that GrB-secreting B cells are playing in the immune system may allow for the development and improvement of novel immunotherapeutic approaches against infectious, autoimmune and malignant diseases.

Figure 1. Possible immunological functions of granzyme B-secreting B cells. B cell-derived granzyme B (GrB) in the context of interleukin-21 (IL-21) stimulation and B-cell receptor (BCR)-engagement may mediate the following functions. (A) The direct, specific and MHC-independent recognition of antigens may stimulate cytotoxic or B cells with antiviral properties, particularly during the early phases of infections. (B) The leakage of GrB in the cytoplasm may result in the apoptotic demise of autoreactive B cells. (C) B cells may acquire a regulatory phenotype, involving GrB expression, that results in suppressive effects on other immune cells.

Figure 2. CD40 ligation regulates IL-21-induced differentiation of B cells into either plasma cells or granzyme B-secreting cells. Partial CD4⁺ T-cell activation. In the early phase of an immune response (0–3 d), a broad spectrum of low-affinity and partly self-reactive CD4⁺ T cells are present in a pre-activated state and secrete interleukin-21 (IL-21) but do not express CD40L. In this setting, B cells that are activated by specific B-cell receptor (BCR) crosslinking differentiate into granzyme B (GrB)-secreting B cells, owing to CD4⁺ T cell-derived IL-21 in the absence of CD40 ligation (right). Full CD4⁺ T-cell activation. In a later phase (> 5 d), upon additional co-stimulation by professional antigen-presenting cells (APCs) in the draining lymph nodes, antigen-specific T cells arrive at the site of inflammation in a fully activated state. Such CD4⁺ T cells express both IL-21 and CD40 ligand, supporting the differentiation of activated B cells into plasma cells (left).