Vikas Sharma

Vip Protects Th2 Cells by Downregulating Granzyme B Expression Vikas Sharma

Following antigenic stimulation, CD4+ T cells differentiate into Th1 and Th2 effectors, with different cytokine profiles and different physiological functions. However, regardless of the initial Th1/Th2 balance, the final immune response depends to a large degree on the regulation of Th1 or Th2 survival under specific conditions. The major purpose of this thesis was to identify and characterize the molecular mechanisms for the protective effect of VIP on Th2 effectors in an in vitro system. Our experiments revealed a surprising new mechanism involved in Th1/Th2 AICD, i.e. the induction of enzymatically active granzyme B (GrB) upon T cell receptor restimulation. In wild-type Th1 and Th2 cells, apoptosis is mediated through both Fas signaling and GrB induction. In lpr (Fas mutant) Th1 and Th2 effectors T cell receptor restimulation results in apoptosis mediated solely by GrB, suggesting that GrB induction is independent of Fas signaling. VIP induces the survival of wild-type Th2 effectors by preventing the induction of GrB and the upregulation of FasL expression in Th2, but not Th1 cells.