IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection

IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and T(FH) cells, IL-21 plays a pivotal role in promoting T(FH) differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes T(FH) differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified T(FH) inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates T(FH) differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of T(FH) responses during respiratory virus infection.