Gene expression profile at single cell level of rotavirus specific CD4+ T cells

IgA is the dominant antibody isotype secreted into the mucosal lumen. Mucosa-resident IgA+ plasma cells (PCs) generated following enteric infection can persist as long-lived plasma cells (LLPCs) in the gut, ensuring durable protection against reinfection. However, little is known about how virus-specific IgA+ PCs are generated and maintained. Upon infection with mouse rotavirus (RV) via the oral route, we found that antigen (Ag)-specific IgG+ and IgA+ PCs are generated in a follicular helper T (TFH) cell-dependent manner that involves CD40 signaling and MHC class II (MHCII) restricted Ag-presentation by B cells. Unexpectedly, although the RV-specific IgG response requires Ag-presentation by conventional dendritic cells, Ag-presentation by B cells is sufficient for the generation of RV-specific IgA. The accumulation of RV-specific IgA+ PCs in the small intestinal lamina propria (SILP) was found to depend on a type 1 TFH (TFH1) cell subset, which requires B cell Ag-presentation for their development and co-expresses Bcl-6 and T-bet. IFNγ receptor signaling is required for the expression of CXCR3 on RV-specific IgA+ PCs, which in turn promotes their migration to the SILP. Moreover, TFH1 cells are also required for the optimal development of IgA+ LLPCs in the upper and lower respiratory tracts in response to intranasal influenza A virus (IAV) infection. However unlike with RV, expression of MHCII on B cells was not sufficient for generating an IAV-specific IgA response in the airways, suggesting the operation of mucosal site-specific priming mechanisms. Collectively, our data reveal that unconventionally primed TFH1 cells support IgA responses to mucosal viral infections.