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Abstract
The production of IL-21 by T follicular helper (Tfh) cells is vital in driving the germinal centre reaction and high affinity antibody formation. However, the degree of Tfh cell heterogeneity and function is not fully understood. We used a novel IL-21eGFP reporter mouse strain to analyze the diversity and role of Tfh cells. Through the analysis of GFP expression in lymphoid organs of IL-21eGFP mice, we identified a subpopulation of GFP+, high IL-21 producing Tfh cells present only in Peyer’s Patches. GFP+Tfh cells were found to be polyclonal and related to GFP−Tfh cells of Peyer’s Patches in TCR repertoire composition and overall gene expression. Studies on the mechanisms of induction of GFP+Tfh cells demonstrated that they required the intestinal microbiota and a diverse repertoire of CD4+ T cells and B cells. Importantly, ablation of GFP+ cells resulted in a reduced frequency of Peyer’s Patches IgG1 and germinal center B cells in addition to small but significant shifts in gut microbiome composition. Our work highlights the diversity among IL-21 producing CD4+ Tfh cells, and the interrelationship between the intestinal bacteria and Tfh cell responses in the gut.
Highlights
T follicular helper (Tfh) cells are crucial to the development of T cell-dependent antibody responses[1,2]
IL-21 is essential for optimal B cell responses, supporting germinal centers (GC) B cell proliferation and plasma cell differentiation while promoting class switching to IgG, and inhibiting class switching to IgE12–14
In contrast to data obtained with other IL-21-reporter mice[31,32,33], GFP expression in IL-21eGFP mice was restricted to a subpopulation of CD4+ T cells in Peyer’s Patches (PP)
Summary
T follicular helper (Tfh) cells are crucial to the development of T cell-dependent antibody responses[1,2] These activated CD4+ T helper cells establish cognate interactions with B cells within lymphoid follicles and germinal centers (GC) to mediate affinity maturation and differentiation of memory B cells and plasma cells. Germ-free mice exhibit under-developed gastrointestinal associated lymphoid tissue (GALT) and small PP28, while manipulating specific microbial populations in the gut using antibiotics can impact the induction of mucosal Th17 and Treg cells[29,30]. To date little is known about the induction, repertoire and functional heterogeneity of Tfh populations in the gut In particular it is not known if different Tfh populations mediate production of IgA and IgG in the gut
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