Determining the impact of HLA type and chronic viral infection on peripheral T-cell receptor sharing between unrelated individuals

Abstract

Abstract T cells generate highly diverse T-cell receptors (TCRs) to recognize antigens, most of which are private to each individual. TCRs with low junctional complexity have a higher likelihood of being generated and shared across individuals. Additional factors that may further limit diversity and increase the likelihood that particular TCRs are public include: (a) thymus selection for maturation of TCRs that bind antigens presented by an individual’s human leukocyte antigen (HLA) proteins, and (b) T-cell proliferation upon exposure to cognate antigens, which remain in the periphery as memory T cells. Numerous public TCRs have been associated with particular HLA restrictions and antigen specificities1. Chowell et al. also showed that HLA diversity is important for mounting an effective T-cell response against solid tumors2. However, little is known about the impact of these forces on the diversity of the TCR repertoire and expected TCR sharing across individuals. Here, we leverage the TCR repertoires of 666 healthy individuals sequenced with the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle, WA) to address these questions. We investigate (a) how HLA restriction affects immune repertoires by examining the effect of HLA heterozygosity and divergence on the diversity of the TCR repertoire; (b) how the similarity of HLA alleles between individuals impacts the number of TCRs shared between individuals and (c) the impact of shared antigen exposure by determining how age and CMV status impacts clone sharing between individuals. These data show that HLA type, age, and CMV exposure shape the immune repertoire and influence the sharing of clones between individuals.