Examining the origin of peripheral self-reactive T cells and the contribution of Gadd45beta to T cell selection events in the HYcd4 TCR transgenic mouse model

Abstract

Thymic negative selection is important for preventing self-reactive T cells from entering the circulation. However, some self-reactive T cell clones can escape negative selection and induce autoimmunity. The molecular pathways that regulate negative selection are currently unclear, but PD-1 and Gadd45β have been implicated. Using the HYcd4 mouse model, we found an absence of self-reactive CD8SP thymocytes, but the presence of self-reactive T cells in the periphery in adult mice. Ontogeny studies demonstrated the presence of self-specific DP and CD8+ T cells in the periphery at Day 3 post-birth that expressed the co-inhibitory receptor PD-1. The presence of self-reactive T cells was not dependent on negative selection occurring in a neonatal thymus. By studying Gadd45β deficient mice, no evidence was found to support a role for Gadd45β in negative selection. Collectively, these data shed light on the source of self-reactive peripheral T cells and the molecular mechanism underlying negative selection.