Opposing development of cytotoxic and follicular helper CD4 T cells controlled by the TCF-1-Bcl6 nexus

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Abstract

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.