Different roles for Smad4-dependent and independent TGFβ signaling pathways during the differentiation of virus-specific effector CD8 T cells (IRM4P.494)

Abstract

Abstract Transforming growth factor-β (TGFβ) is a regulatory cytokine that modulates the activities of other cells via multiple signaling pathways. The predominant pathways in hematopoietic cells are mediated by Sma and Mad-related family members (SMAD) and depend on a ubiquitous activating protein SMAD4. Other Smad4-independent pathways can also be activated by TGFβ however their role in immune regulation is less clearly defined. We examined the role of Smad4-dependent and -independent TGFβ signaling during the development of the CD8 T cell response to influenza virus infection. Our studies show that a complete blockade of all TGFβ-signaling accelerates the development of virus-specific CD8+ effector T cells (Teff) which express KLRG-1 and produce large quantities of cytokines in the lungs. In contrast, selective inhibition of only Smad4-dependent signaling prevents the development of a robust Teff response. These data point to a previously unexamined role of Smad4-independent TGFβ signaling in the regulation of virus-specific Teff cells. We are using this model to determine whether TGFβ regulation plays an major role in protective immunity in the lungs.