54: Role of transforming growth factor-beta signaling in CD8+ T cells in mucosal anti-viral immune responses

Abstract

Under steady-state, the gut balances regulatory and inflammatory processes in order to preserve membrane integrity while preventing autoimmunity or inappropriate inflammation to commensal bacteria and innocuous food antigens. However, the vast majority of sexually transmitted infections also occur via a tolerogenic mucosal barrier. In such infections, the cytotoxic T lymphocyte (CTL) response is often “too late and too little” to induce protective immunity in most individuals. Transforming growth factor (TGF)β is highly abundant in the intestinal milieu. The decision to break tolerance in favor of immunity in mucosal tissues is likely regulated by a balance between levels of TGFβ and inflammatory cytokines. Our work demonstrates that immunosuppressive effects of TGFβ are subdued in the presence of high inflammatory signals; however, in the absence of strong inflammation and co-stimulatory signals, TGFβ inhibits proper T cell activation. The innate and adaptive immune responses are most likely dampened during sexual transmission of pathogens, in part due to high concentrations of TGFβ in mucosal tissues. To study the role of TGFβ signaling in mucosal anti-viral immunity, we established a rectal viral transmission model in mice using lymphocytic choriomeningitis virus (LCMV). Compared to systemic infections, the kinetics and the magnitude of the CD8 T cell response are much reduced upon rectal LCMV infection. To assess the role of TGFβ in mucosal immunity generated during rectal LCMV infection, we adoptively co-transferred LCMV-specific CD8 T cells (P14), carrying wildtype TGFβ receptor II (TGFβRII WT) and those deficient in this receptor (TGFβRII KO), into wild type hosts. The animals were then infected rectally with LCMV. We will present data on the mechanism by which TGFβ affects activation and expansion of effector CD8 T cells, their migration into the gut tissues, as well as their ability to perform cytolytic function and become tissue-resident memory T cells.