A major theme of our research program deals recent data that strongly suggests that CD8+ T cells interact with CD4+ T cells to down-regulate CD4+ T cell mediated immune responses in both normal conditions and during the evolution of autoimmune states. These regulatory interactions between CD8+ T cells regulating CD4+ T cells are complex and may involve both antigen specific as well as non-specific mechanisms. We have explored a model in which T cell receptor related structures such as TCR-derived peptide/MHC complexes expressed on antigen activated CD4+ T cells induce CD8+ T regulatory cells. These CD8+ T cells differentiate and recognize the TCR-derived peptide/MHC class I complexes expressed on the activated CD4+ inducer cells. The effector phase of regulation mediated by these putative TCR peptide recognizing CD8+ T cells could either be by direct cytolysis and/or the release of cytokines. For example, we showed that CD8+ T cells regulate the autoimmune response mediated by CD4+ T cells in murine models of multiple sclerosis. These experiments employed the EAE model in which mice immunized with an encephalitogenic peptide develop autoimmune disease similar to human MS and recover. Importantly, the first episode of EAE renders the animals resistant to the re-initiation of EAE by secondary immunization. In contrast, animals depleted of CD8+ T cells in vivo, are no longer resistant to a second induction of disease with MBP. These data demonstrate that CD8+ T cells play a major role in the resistance to a second induction of EAE. Further analysis of the specificity of this regulation showed that CD8+ T cell recognition of TCR Vb determinants expressed on CD4+ T cells were critical to the induction and effector phases of this regulation. These studies have recently been extended to the analysis of immune regulation in patients with inflammatory arthritis and systemic lupus in man. In fact, current studies are following these patients during therapy with immunosuppressive agents like anti-CD40L antibodies.