Date of Completion


Embargo Period


Major Advisor

Linda Cauley

Associate Advisor

Stefan Brocke

Associate Advisor

Anthony Vella

Field of Study

Biomedical Science


Doctor of Philosophy

Open Access

Open Access


Transforming growth factor β (TGFβ) is an immunosuppressive cytokine with multiple functions in the immune system, including regulation of cytotoxic T lymphocytes. This thesis will examine how TGFβ, and the downstream signaling molecule Smad4, alter the CD8 T cell response to infection with different strains of influenza A virus (IAV). Chapter III shows how TGFβ and Smad4 regulate the phenotype, localization and function of antigen-specific CD8 T cells in the lungs. Our data reveal a previously unappreciated role of Smad4 in regulating effector and memory CD8 T cell differentiation independently of TGFβRII. Specifically we find that Smad4 promotes terminal differentiation of KLRG1+ T effector (TEFF) cells, a subset that is inhibited by TGFβ. Smad4 and TGFβ also play reciprocal roles in regulation of CD103+ tissue resident memory T (TRM) cells and CD62L+ central memory T (TCM) cells. Altered expression of multiple homing receptors changes the distribution of antigen-specific CD8 T cells in vivo, and therefore impacts viral clearance during primary viral infection and heterosubtypic immunity. Chapter IV explores the mechanism by which Smad4 regulates the CD8 T cell response, by examining the global transcription profile, cellular metabolism and signaling pathways of mutant and wild type CTLs. Our data suggests that Smad4 is activated by a novel pathway to promote terminal differentiation of effector T cells possibly through enhancing IL-12 signaling and T-bet expression, and inhibiting OXPHOS activity. Also, by enhancing T-bet and Eomesodermin, Smad4 may act as a suppressor of CD103 and later promotes re-expression of CD62L. This novel pathway of Smad4 ligand is counter-regulated by TGFβ, possibly by competing for Smad4 with phosphorylated Smad2/3. Our study sheds new light on the signals that regulate the differentiation and distribution of virus-specific CD8 T cells during IAV infection, which can be utilized to optimize cell-mediated immunity during the design of IAV vaccine.