REGULATION OF IMMUNE RESPONSES BY VBETA SPECIFIC CD8+ T CELLS

We have identified CD8+ CTL that recognize framework portions of Vbeta along with the class I-b MHC molecule Qa-1. These CD8+ cells are shown to arise in mice during the response into superantigen or after immunization of mice with activated CD4+ cells. In vitro, these CD9+ T cells kill activated CD4+ T cells in a Vbeta-specific manner. Because Qa-1 is an activation molecule on T cells and became CD9+ T cells have been shown to regulate CD4+ T cells , it is envisioned that these Qa-1 restricted, CD8 anti-Vbeta T cells serve to regulate activated CD4+ cells. This project extends the analysis of afferent mechanisms in T cell vaccination in project #2 to the study of effector mechanisms used by CD8 anti-Vbeta T cells. We will focus on animal models of autoimmunity in which CD9+ cells regulate the autoimmune process of in which defective killing by T cells contributes to t he etiology of autoimmunity. For example, animals with defects in FasL have autoimmunity and also have defects in DEB-mediated, Vbeta-specific T cell deletion, phenomenon associated with the CD8 anti- Vbeta response. In this project, we will directly investigate mechanisms whereby CD8 antiVbeta cells kill and extend these studies to the Fas/FasL system to determine whether defects in CD8-mediated killing contribute to the autoimmune syndrome exhibited by Fas and FasL mutant mice. CD8+ T cells have also been shown in the EAE model, to regulate disease and prevent relapse. We will directly study effector mechanisms used buy CD8+ T cells to regulate encephalitogenic T cells in EAE. Will determine if CD8 anti-Vbeta T cells distinguish between TH subsets and if CD9+ T cell regulation in EAE accounts for the observation that, during remission, there is a skewing of the immune response towards a TH2 phenotype. Lastly, we have hypothesized that CD8 anti-Vbeta cells specifically participate in vivo in the regulation of EAE. As a direct test of this hypothesis we will identify TCR signatures expressed by CT8 anti-Vbeta8 T cells and use these signatures to follow the expansion of this population of CD8+ cells first after immunization of mice with Vbeta9+CD4+ cells and, most importantly, during EAE. Our ability to identify these CD8+ T cells in vivo during EAE would implicate CD8 and anti-Vbeta cells as an effector CD9+ population responsible for regulating EAE.