The cytokine-mediated regulation of human B-cell differentiation.

The primary function of B cells is the secretion of antigen-specific antibody. The maturation of naïve B cells into plasmablasts capable of secreting high affinity antibody is achieved by the integration of signals from the B-cell receptor, T-cell costimulatory molecules and cytokines. Many different cytokines, including IL-4, IL-6, IL-10, IL-13, IL-21, BAFF and APRIL, influence B-cell maturation in various ways, but the mechanisms underlying the distinct effects of these cytokines on the behaviour of human B cells has yet to be fully elucidated. Most cytokines exert their biological effect by binding to a specific receptor and initiating downstream signalling events, which culminate in altered gene transcription. The common gamma chain (γc), JAK3 and STAT3 are important components of the signalling cascades initiated by many cytokines with potent effects on human B cells. Individuals with immunodeficiency syndromes due to single gene defects in these pathways provide a unique opportunity to study cytokine responses in human B cells. We have examined naïve B cells from patients with Autosomal Dominant Hyper-IgE Syndrome (AD-HIES) due to STAT3 mutations, Severe Combined Immunodeficiency (SCID) with IL2RG or JAK3 mutations, CD25-deficiency due to IL2RA mutations, and IL-21R deficiency, to clarify the roles of STAT3, γc, and IL-21 in cytokine-induced responses of human B cells.We have identified IL-21 as the primary γc-binding cytokine required for human B-cell differentiation in vivo. Although B-cell cytokines are highly pleiotropic, the role of IL-21 appears to be non-redundant, as IL-21 can simultaneously achieve the effects of many different cytokines on B-cell proliferation, isotype switching, memory cell formation, differentiation to plasma cells and antibody secretion. We have also identified many STAT3-dependent genes induced by IL-21 in normal B cells, which may contribute to the humoral immunodeficiency in patients with AD-HIES. Specifically, we demonstrated that IL-21, signalling via STAT3, induces expression of the IL-2α receptor on B cells, thus sensitising them to the stimulatory effects of IL-2. A greater understanding of B-cell cytokine responses may lead to enhanced therapeutics, not only in the form of more targeted treatments for patients with clinical immunodeficiencies, but also in terms of immunisation responses and autoimmunity