IL-21 from IFN-g +IL-21 +hybrid T cells promotes germinal center B cell proliferation

Abstract

Abstract Clearance of infection with Plasmodium spp. requires both antibody and Th1-type responses. While Th1-like cells control the peak in P. chabaudi infection, however specific IgG is delayed. Both Tfh and GC-Tfh can promote specific antibodies and long-lived plasma cells to fully clear infection. GC-Tfh numbers remain stable throughout P. chabaudi infection, while Th1/Tfh hybrid (IFN-g +/IL-21 +CXCR5 int) cells expand. Testing if triple cytokine reporter mice (Il21-Kat Il4-GFP Ifng/Thy1.1 Knock-In) report Tfh functionality accurately, we confirmed that Tfh-like Il-21 +Ifng −cells were enriched for GC Tfh (CXCR5 hiPD-1 hiCXCR6 −) while the majority of Ifng +Il21 +cells were CXCR5 intCXCR6 +. GC-Tfh appear functional sooner than Ifng +Il21 +with expression of CCR7 intand Il4 +as early as day 5p.i. Transfer of cytokine-expressing subsets from triple reporter and Il21 −/−Ifng-Thy1.1 KI mice into T cell deficient recipients, which are then infected with P. chabaudi, also shows that Il21 +Ifng −Tfh-like cells from day 8 of P. chabaudi infection are functional. Il21 +Ifng −cell recipients generated more GC B cells, larger GCs and more parasite-specific IgG compared to other groups. Il21 +Ifng +hybrid T cells, also promoted GCs, but Th1-like Ifng +T cells from WT or Il21 −/−mice did not. As GCs were larger, but not more numerous, in Il21 +Ifng −recipient spleens, we hypothesized that B cell proliferation was increased. Indeed, there were more BrdU +dark zone (CXCR4 +CD86 −) GCB cells in recipients of Il21 +Ifng −cells than other groups, particularly recipients of Ifng +T cells from IL-21 KO. Combined, this data suggests that IL-21 from hybrid Th1/Tfh promotes GCB cells in vivo, though less than Il21 +Ifng −T cells. R01AI13506101