The MMTV envelope glycoprotein promotes the survival and function of CD8 T cells during chronic viral infection and cancer via ITAM-dependent signaling 3439

Abstract Description Transposable elements (TEs) comprise ∼50% of the genome, yet their contributions to normal physiology beyond embryonic development are poorly understood. We hypothesized that TEs may regulate developmental processes in CD8 T cell differentiation. Here we identify an envelope glycoprotein (env) encoded by the murine mammary tumor virus MMTV that promotes the survival and function of exhausted T cells (TEX) via ITAM-dependent signaling. Analysis of TE expression across CD8 T cells revealed that endogenous MMTV is upregulated upon TEX differentiation. MMTV knockdown depletes TEX precursor cells early in LCMV clone 13 infection. Single-cell RNA analysis of MMTV knockdown cells suggested a role for MMTV preceding the early bifurcation of TCF1+ TEX precursor cells and Tim3+ effector-like cells. Accordingly, the MMTV env is co-expressed with costimulatory/inhibitory receptors within the first days of LCMV infection and also in B16OVA melanoma tumors. Overexpression of the MMTV env in OT1 T cells enhances control of B16OVA in vivo. Mutation of the MMTV env ITAM abrogates the env-dependent benefit on tumor control. Altogether our data suggest that the MMTV env ITAM promotes TEX survival and differentiation. These studies reveal an unexpected role for a TE-encoded protein in CD8 T cells and highlight one way that mammalian genomes have coopted physiological functions for endogenous retroviruses. Moreover, this work suggests a potential to exploit this ITAM signal for therapeutic gain. Funding Sources This work was supported by the Parker Institute for Cancer Immunotherapy and the Mark Foundation for Cancer Research. Topic Categories Viral Immunology (VIR)