Cytokines in the germinal centre reaction to T-dependent antigen

Abstract

During the germinal centre (GC) response to T-dependent antigen B cells undergo the processes of somatic hypermutation and affinity maturation to become high-affinity antibody producing plasma cells or memory B cells. While the GC B cells undergo these processes they are crucially dependent on help from T cells located within the follicle. These T follicular helper (Tfh) cells provide help in the form of cell-to-cell interaction as well as the secretion of cytokines.Our studies focused on the crucial role cytokines play in the GC reaction, with a special focus on the important but antagonizing roles of the cytokines IL-2 and IL-21. We were able to describe a novel T cell intrinsic mechanism of IL-21 restricting the expansion of regulatory T cells and the follicular regulatory T (Tfr) cell subset via the Bcl-6 mediated inhibition of responsiveness to IL-2. The absence of IL-21 not only led to increased regulatory T cell and Tfr populations in vivo, but also we could also show the increased expression of the alpha subunit of the high-affinity IL-2R (CD25), this was especially apparent on Il21r-/- Tfr cells. Furthermore, we discovered the ability of IL-21 to influence CXCR4 expression on both follicular and extrafollicular T helper cell subsets, as well as GC B cells. With the help of a novel mouse model, with a single point mutation in the cytosolic part of the IL-21R, leading to a STAT1-specific IL-21 signalling defect, we were able to investigate the relative importance of IL-21 mediated STAT1 and STAT3 activation during the GC response to T-dependent antigen. These Il21rEINS mice enabled uncover a regulatory role of IL-21 mediated STAT1 activation on the Tfr cell population. Astonishingly, we also detected a crucial cell intrinsic function of IL-21 dependent activation of STAT1 for the differentiation and function of Tfh cells. This exacerbated Tfh phenotype in Il21rEINS mice in comparison to Il21r-/- mice might be explained by compensatory mechanisms mediated by other cytokines, such as IL-6, at work in the total absence of the IL-21R, but not when a partially functional receptor is still present