TCR Affinity for Self-Ligands Influences the Development and Function of Encephalitogenic T Cells

The specificity and affinity of self-reactive T cells is likely to impact the development of autoimmune-disease causing T cells in the thymus as well as their function in the periphery. We identified a naturally occurring, low affinity variant of an MBP Ac1-11/I-Au specific TCR that is known to induce EAE. Thymocytes in mice carrying the transgenes for this low affinity TCR were poorly positively selected, as compared to their high affinity TCR expressing counterparts. Nonetheless, CD4 T cells bearing the low affinity TCR accumulated in the periphery of the mice. Unlike mice expressing the high affinity TCR, these mice very rarely developed disease. However, if endogenous TCR expression was eliminated by breeding to RAG1 deficient mice, 100% of the mice carrying either the high or the low affinity versions of the TCR developed EAE. Intriguingly, while the incidence of EAE increased, the age of onset of disease in both mice was identical. These data suggest disease onset occurs during a short window of mouse development.