Multiple sclerosis (MS) is an inflammatory, demyelinating, central nervous system disease mediated by myelin-specific T cells. Environmental triggers that cause a breakdown of myelin-specific T cell tolerance are unknown. We found that CD8+ myelin basic protein (MBP)-specific T cell tolerance can be broken and autoimmunity induced by infection with a virus that does not express MBP cross-reactive epitopes and does not depend on bystander activation. Instead, the virus activated dual T cell receptor (TCR)-expressing T cells capable of recognizing both MBP and viral antigens. These results demonstrate the importance of dual TCR T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected individuals, as hypothesized in the etiology of MS.

Myelin presentation to T cells within the central nervous system (CNS) sustains inflammation in multiple sclerosis (MS). CD4+ and CD8+ T cells contribute to MS; however, only cells that present myelin to CD4+ T cells have been identified. We show that MHC class I-restricted myelin basic protein (MBP) was presented by oligodendrocytes and cross-presented by Tip-dendritic cells (DCs) during experimental autoimmune encephalomyelitis (EAE), an animal model of MS initiated by CD4+ T cells. Tip-DCs activated naïve and effector CD8+ T cells ex vivo, and naïve MBP-specific CD8+ T cells were activated within the CNS during CD4+ T cell-induced EAE. These results demonstrate that CD4+ T cell-mediated CNS autoimmunity leads to determinant spreading to myelin-specific CD8+ T cells that are capable of direct recognition of oligodendrocytes.

Many antigens recognized by tumor-reactive cytotoxic CD8 + T cells are self-antigens. Tyrosinaserelated protein 2 (TRP-2) is a melanogenic enzyme expressed by both melanocytes and melanomas that is reported to be a candidate melanoma rejection antigen. To study the role of self-reactive CD8 + T cells in tumor immunity and autoimmunity, we generated mice which bear a T cell receptor transgene (TCR Tg) specific for the TRP-2 (180-188) epitope. TRP-2 TCR Tg mice did not spontaneously develop depigmentation despite systemic expression of TRP-2 in the skin. Peripheral T cells from these TCR Tg mice exhibited a naïve phenotype and proliferated in response to TRP-2 in vitro. In addition, transfer of in vitro-activated Tg T cells reduced B16 pulmonary tumor burden, but not subcutaneous tumors. We next sought to determine the in vivo responses of the Tg T cells to endogenous and tumor-derived TRP-2. Adoptive transfer of naïve TCR Tg T cells into wild-type C57BL/6 mice, in combination with a TRP-2-pulsed dendritic cell vaccine, induced proliferation of the Tg T cells and resulted in migration of the Tg T cells into a subcutaneous B16 melanoma tumor. Although these tumor-infiltrating Tg T cells remained reactive against TRP-2, they did not reduce growth of the primary subcutaneous tumor; similarly, these in vivo-primed effector cells had no significant effect on growth of pulmonary nodules. These data demonstrate that despite in vivo priming, tumor-infiltrating T cells may fail to reduce tumor burden. Determining the basis for the inability of the tumor micro-environment to sustain effective anti-tumor responses will be critical for designing newer, more potent anti-tumor immunotherapies.