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

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.

Keywords: CD4 T cell differentiation; adenovirus-based vaccination; antiviral immunity; cytotoxic CD4 T cells; inhibitory receptors; retroviral infection; single-cell RNA sequencing.