UC San Diego

The T cell receptor (TCR) plays a crucial role in T cell development, response, and homeostasis. A small population of T cells naturally express two TCRα clonotypes (dual TCRα cells). The study of dual TCRα cells had been limited by the lack of tools available to definitively identify them. A transgenic B6.TCRA-GFP/RFP mouse model linking fluorophores to TCRα constant region to enable identification of dual TCRα cells was developed by our lab. In Chapter 1, I hypothesized that dual TCRα cells influence immune response against foreign antigens. LCMV-Armstrong infection model revealed that dual TCRα cells expanded significantly from pre-infection baseline of ~18% to 40-50% of virus-specific T cells at 8 dpi. Dual TCR frequency at 28 dpi remained higher than pre-infection among LCMV-specific CD4+ effector memory and central memory subsets. These findings demonstrate that dual TCRα expression influences protective antiviral responses.In Chapter 2, I hypothesized that dual TCRα cells contain a distinct repertoire of receptors. Bulk sequencing revealed that peripheral dual TCR repertoire contained unique clonotypes not found in the single TCR repertoire. Relatively low correlation, similarity, and overlap were observed between the single and dual TCR clones. The CD4+ dual TCRα repertoire was enriched for clones associated with autoantigen epitopes. These results support my hypothesis that the dual TCR repertoire contains unique clonotypes and suggest that dual TCRα cells may have increased potential for autoreactivity. Altogether, these findings demonstrate that dual TCR cells play a critical role in mediating antiviral immunity and T cell repertoire formation.