Characterizing the Role of the T Cell Receptor Repertoire in T Cell Development and Function

Expansion and memory of immune cells in response to stimulation of diversified antigen receptors is the hallmark of adaptive immunity. Here, we use antigen receptor sequencing and in vivo analysis of monoclonal cell populations to elucidate the development and function of two T cell populations: Foxp3+RORγt+ CD4+ T cells and γδ T cells. Foxp3+RORγt+ T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relation to RORγt- Treg and RORγt+ TH17 cells remains unclear. Here, we show that despite sharing a subset of TCR specificities with TH17 cells, Foxp3+RORγt+ T cells first acquire a Foxp3+RORγt- phenotype before co-expressing RORγt, suggesting that Foxp3+RORγt+ cell development can occur via an RORγt- Treg intermediate. While γδ T cells are considerably well studied relative to Foxp3+RORγt+ T cells, the importance antigen receptor diversification to γδ T cell function is still poorly understood. In order to comprehensively assess the paired-chain γδ T cell repertoire during inflammation, we developed a fixed-TCRδ system. We show that experimental autoimmune encephalomyelitis (EAE) results in dramatic clonal expansion of γδ T cells and that a single expanded TCR clone is sufficient to exacerbate immune pathology. Together, this suggests that γδ T cells can exhibit the clonal expansion characteristic of an adaptive immune response and that this response is physiologically significant to the outcome of EAE