Differential Requirements for Tcf1 Long Isoforms in CD8⁺ and CD4⁺ T Cell Responses to Acute Viral Infection

In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long-term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal β-catenin-interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms. During CD8⁺ T cell responses, Tcf1 long isoforms were dispensable for generating cytotoxic CD8⁺ effector T cells and maintaining memory CD8⁺ T cell pool size, but they contributed to optimal maturation of central memory CD8⁺ T cells and their optimal secondary expansion in a recall response. In contrast, Tcf1 long isoforms were required for differentiation of T follicular helper (T_FH) cells, but not T_H1 effectors, elicited by viral infection. Although Tcf1 short isoforms adequately supported Bcl6 and ICOS expression in T_FH cells, Tcf1 long isoforms remained important for suppressing the expression of Blimp1 and T_H1-associated genes and for positively regulating Id3 to restrain germinal center T_FH cell differentiation. Furthermore, formation of memory T_H1 and memory T_FH cells strongly depended on Tcf1 long isoforms. These data reveal that Tcf1 long and short isoforms have distinct, yet complementary, functions and may represent an evolutionarily conserved means to ensure proper programming of CD8⁺ and CD4⁺ T cell responses to viral infection.