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

Abstract

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.

Keywords: 1C6; EAE (experimental autoimmune encephalomyelitis); FoxP3; RAG; TCR transgenic mice; Treg—regulatory T cell; allelic exclusion; non-obese diabetic (NOD).