Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8+ TCR Repertoires to Immunodominant Viral Antigens

Abstract

Summary: A diverse T cell receptor (TCR) repertoire is essential for controlling viral infections. However, information about TCR repertoires to defined viral antigens is limited. We performed a comprehensive analysis of CD8+ TCR repertoires for two dominant viral epitopes: pp65495–503 (NLV) of cytomegalovirus and M158–66 (GIL) of influenza A virus. The highly individualized repertoires (87–5,533 α or β clonotypes per subject) comprised thousands of unique TCRα and TCRβ sequences and dozens of distinct complementary determining region (CDR)3α and CDR3β motifs. However, diversity is effectively restricted by preferential V-J combinations, CDR3 lengths, and CDR3α/CDR3β pairings. Structures of two GIL-specific TCRs bound to GIL–HLA-A2 provided a potential explanation for the lower diversity of GIL-specific versus NLV-specific repertoires. These anti-viral TCRs occupied up to 3.4% of the CD8+ TCRβ repertoire, ensuring broad T cell responses to single epitopes. Our portrait of two anti-viral TCR repertoires may inform the development of predictors of immune protection. : CD8+ T cells are essential for controlling viral infections. Chen et al. analyzed human TCR repertoires specific for two viral epitopes. Repertoire diversity was much greater than previously appreciated for both public and private TCRs. Such diversity assures protection from virus escape and the provision of T cell functional heterogeneity. Keywords: αβ TCRs for IAV-GIL, αβ TCRs for CMV-NLV, TCR repertoire, TCR-pMHC structure, CD8 T cells, human