T Cell Receptor αβ Diversity Inversely Correlates with Pathogen-Specific Antibody Levels in Human Cytomegalovirus Infection

CD8+ T cell diversity may be more important than T cell abundance in limiting the negative consequences of cytomegalovirus persistence. Size Doesn’t Matter There is now a solution to the endless debate about the relative merits of size and performance—size doesn’t matter so much after all, at least to the immune response to human cytomegalovirus (CMV). Wang et al. show that the diversity of the CD8+ TCRαβ repertoire may be more important than T cell abundance in limiting the negative consequences of CMV persistence. CMV infection is frequently asymptomatic in healthy people, but can be quite dangerous in immunocompromised populations, including people infected with HIV, organ transplant recipients, and newborns. After acute infection, human CMV goes into hiding, staying in an individual for the rest of his or her life; however, continued infection is indicated by the presence of antibodies. Although a diverse repertoire of T cells has long been thought to be critical for pathogen control, the actual importance of repertoire diversity in controlling human infection remained unproven. Wang et al. directly examined this question in human patients with human CMV infection. The authors used a single-cell strategy for the clonotypic analysis of human CD8+ TCRαβ repertoires and found that the repertoire diversity, but not the magnitude, of the T cell response was inversely related to antibody levels. The single cell–based approach to TCR repertoire analysis enabled detailed characterization of epitope-specific CD8+ T cell clonotypes as they persist in vivo. These data suggest that expanding diversity is a critical target for immunotherapy. Apparently, William Cowper was right, “Variety’s the very spice of life”—and of the immune system as well. 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.