Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

CD4(+) T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8(+) T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4(+) T cells. However, the conditions that induce CD4(+) CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB)(+) CD4(+) CTLs, which distinguishes them from other CD4(+)T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4(+) CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4(+) CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4(+) T cells with either helper or killer functions.