T cell receptor αβ diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection

A diverse T cell receptor (TCR) repertoire capable of recognizing a broad range of antigenic peptides is thought to be central to effective pathogen-specific immunity by counteracting escape mutations, selecting high-avidity T cells, and providing T cell specificities with comprehensive functional characteristics. However, evidence that TCR diversity is important for the successful control of human infections is limited. A single-cell strategy for the clonotypic analysis of human CD8 ⁺ TCRαβ repertoires was used to probe the diversity and magnitude of individual human cytomegalovirus (CMV) - specific CD8 ⁺ T cells recovered directly ex vivo. We found that CD8 ⁺ TCRαβ repertoire diversity, but not the size of the CD8 ⁺ T cell response, was inversely related to circulating CMV-specific antibody levels, a measure that has been correlated epidemiologically with differential mortality risks and found here to be higher in persons with detectable (versus undetectable) CMV viral loads. Overall, our findings indicate that CD8 ⁺ T cell diversity may be more important than T cell abundance in limiting the negative consequences of CMV persistence, demonstrate high prevalence of both TCRα and TCRβ public motif usage, and suggest that a highly diverse TCRαβ repertoire may be an important benchmark and target in the success of immunotherapeutic strategies.