CD7 drives CD8 T cell exhaustion during chronic viral infection 3877

Abstract Description Viral persistence is often associated with CD8 T cell “exhaustion”, a differentiation process characterized by co-inhibitory receptor upregulation and loss of effector function. Evidence shows that “exhausted” T cells are comprised of heterogenous populations, including a progenitor subset that transitions through an intermediate state before diverging into either terminally exhausted cells or cytolytic effector cells crucial for viral control. However, the mechanisms underlying this bifurcation process remains unclear. Using single-cell RNA-seq, we show that the Ig superfamily member CD7 is selectively upregulated on exhausted T cells during chronic LCMV infection, possibly implicating a role for Cd7 in regulating T cell exhaustion. Notably, using CRISPR Cas-9 to delete Cd7 in TCR transgenic P14 cells, we show that loss of CD7 results in a 3-4-fold increase in effector T cell formation in the spleen, liver, and circulation following chronic LCMV infection. This was accompanied by a reduction in exhausted T cell formation, decreased inhibitory receptor expression, and an augmented capacity to produce IFN-y upon GP33-41 peptide stimulation. Further, in an in vitro model of T cell exhaustion, we demonstrate that deletion of CD7 lowers expression of key exhaustion-programming transcription factors downstream of the TCR, including Nur77 and Tox. Together, our data suggests that CD7 functions to amplify TCR signaling strength and program T cell exhaustion during chronic infection. Funding Sources R00AI153537; T32AI007485 Topic Categories Viral Immunology (VIR)