The CD8+ T cell response to an autoimmune disease-inducing viral infection of the CNS.

摘要

Theiler's murine encephalomyelitis virus (TMEV-IDD) is a model for the human disease Multiple Sclerosis (MS). MS is thought to be autoimmune in nature, thus antigen-specific methods of neutralizing self-reactive T cells are currently being investigated. One such method is ECDI coupled cell tolerance, which is effective and safe for the tolerization of CD4+ T cells in mice. Our studies demonstrated that this method of tolerance was effective for TMEV-specific CD8+ T cells in certain circumstances, and that the mechanism through which it works differs significantly from the established mechanism for CD4+ T cells. Importantly, attempts to induce tolerance of TMEV-specific CD8+ T cells in mice infected with TMEV resulted in a severe, lethal reaction. These results call into question the safety of using CD8 T-cell tolerance to treat human disease.; We further investigated TMEV-specific CD8+ T cells and found that in TMEV-IDD-resistant mice (B6 mice), a lack of TMEV-specific CD8 + T cells did not permit viral persistence and TMEV-IDD, but rather simply delayed viral clearance. In the absence of both B cells and TMEV-specific CD8+ T cells, B6 mice became susceptible to a CNS disease distinct from TMEV-IDD. A lack of the TMEV-specific CD8+ T cell response in mice that are susceptible to TMEV-IDD (SJL mice) had no effect on viral persistence or TMEV-IDD; however, these mice were capable of clearing TMEV and preventing TMEV-IDD if they were administered CD8+ T cell blasts corresponding to the immuno-dominant response several days before the natural response was elicited. Finally, the CD8+ T cell response to TMEV in SJL, but not B6 mice, was demonstrated to be under the control of CD4+ CD25+ regulatory T cells (Treg ). When Treg were absent during the generation of the TMEV-specific immune response in SJL mice, TMEV-IDD disease progression was ameliorated. The results of these studies indicated that the CD8+ T cell response to an autoimmunity-inducing CNS viral infection can be modulated in to permit viral clearance and protect mice from demyelinating disease.