HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

Abstract

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, certain factors such as low junctional diversity, thymic selection, and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCR{beta} variable region of 426 healthy individuals, we find that fewer than 1% of TCR{beta} clones are shared between individuals on average, consistent with largely private TCR{beta} repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCR{beta} clones, with each additional shared HLA allele contributing to an increase in [~]0.01% of the total TCR{beta} clones being shared, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCR{beta} clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCR{beta} clone sharing, indicating that the pattern of private TCR{beta} clonal expansion is a general feature of the T-cell response to other infectious antigens. All of these factors contribute to shaping the TCR{beta} repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.