A Temporal Switch in T Follicular Helper Cells Controls the Output of the GC Response to Influenza

Abstract T follicular helper (Tfh) cells are a specific subset of CD4 T cells that localize in the B cell follicle and are essential for the Germinal Center (GC) response. Under polarizing environments, Tfh cells produce effector cytokines, including IFN-γ and IL-4. Beyond promoting class switching, the role played by the different subsets of cytokine-producing Tfh cells remains largely unexplored. Using an influenza infection model, we show here that Tfh cells switch from producing IFN-γ early after infection to mainly producing IL-4 at later time points. Importantly, IFN-γ and IL-4-producing Tfh cells differently control the GC B cell response to influenza. Whereas IL-4-producing Tfh cells help GC maintenance late after infection, interaction with IFN-γ producing Tfh cells skews the GC B cell response towards the memory differentiation pathway early after infection. Consequently, lung-memory B cells fail to differentiate in the absence of IFN-γ producing Tfh cells. Collectively, our results support a model in which temporary changes in cytokine production by Tfh cells dynamically control the outcome of the GC response. Hence, our data provide new insights into GC fate decisions following influenza infection. Supported by grants from NIH (R56 AI162698, R01 AI110480)