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)([35−55]). 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 × Rag1(−/−) mice profoundly disrupted thymic negative selection and led to a sharp decrease in the number of mature peripheral T cells. 1C6 × Rag1(−/−) mice developed spontaneous EAE at a significant frequency and rapidly developed fatal EAE upon immunization with myelin oligodendrocyte glycoprotein (MOG)([35−55]). Passive transfer of 1C6 × Rag1(+/+) CD4(+) T cells, but not CD8(+) T cells or B cells, partially rescued 1C6 × Rag1(−/−) mice from severe EAE. FoxP3(+) CD4(+) T(reg) cells were present in the CNS of immunized 1C6 mice, as well as immunized 1C6 × Rag1(−/−) that had been supplemented with 1C6 CD4(+) T cells. However, they were not observed in 1C6 × Rag1(−/−) that did not receive Rag1-sufficient 1C6 CD4(+). Further, in vivo blockade of T(reg) accelerated the onset of symptoms in 1C6 mice immunized with MOG([35−55]), indicating the pertinence of T(reg)-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.