Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4⁺ T cells

Differentiation of CD4⁺ T cells into either follicular helper T (T_FH) or type 1 helper T (T_H1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4⁺ T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove T_FH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T_H1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4⁺ T cell differentiation and might instruct vaccine design strategies.