Endogenous T Cell Receptor Rearrangement Represses Aggressive Central Nervous System Autoimmunity in a TcR-Transgenic Model on the Non-Obese Diabetic Background.

The T cell response to central nervous system (CNS) antigen in experimental autoimmune encephalomyelitis (EAE) permits one to model the immune aspects of multiple sclerosis. 1C6 transgenic mice on the non-obese diabetic (NOD) background possess a class II-restricted T cell receptor (TcR; Vα5-Vβ7) specific for the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG). It remains to be determined what role is played by allelic inclusion in shaping the TcR repertoire of these mice. Here, we show that 1C6 T cells display substantial promiscuity in their expression of non-transgenically derived Vα chains. Further, enforced expression of the transgenic TcR in 1C6 × mice profoundly disrupted thymic negative selection and led to a sharp decrease in the number of mature peripheral T cells. 1C6 × mice developed spontaneous EAE at a significant frequency and rapidly developed fatal EAE upon immunization with myelin oligodendrocyte glycoprotein (MOG). Passive transfer of 1C6 × CD4 T cells, but not CD8 T cells or B cells, partially rescued 1C6 × mice from severe EAE. FoxP3 CD4 T cells were present in the CNS of immunized 1C6 mice, as well as immunized 1C6 × that had been supplemented with 1C6 CD4 T cells. However, they were not observed in 1C6 × that did not receive Rag1-sufficient 1C6 CD4. Further, blockade of T accelerated the onset of symptoms in 1C6 mice immunized with MOG, indicating the pertinence of T-mediated control of autoimmune inflammation in this model. Thus, TcR allelic inclusion is crucial to the generation of FoxP3 CD4 T cells necessary for the suppression of severe CNS autoimmunity.