Abstract
T cell discrimination of self and non-self is the foundation of the adaptive immune response, and is orchestrated by the interaction between T cell receptors (TCRs) and their cognate ligands presented by major histocompatibility (MHC) molecules. However, the impact of host immunogenetic variation on the diversity of the TCR repertoire remains unclear. Here, we analyzed a cohort of 666 individuals with TCR repertoire sequencing. We show that TCR repertoire diversity is positively associated with polymorphism at the human leukocyte antigen class I (HLA-I) loci, and diminishes with age and cytomegalovirus (CMV) infection. Moreover, our analysis revealed that HLA-I polymorphism and age independently shape the repertoire in healthy individuals. Our data elucidate key determinants of human TCR repertoire diversity, and suggest a mechanism underlying the evolutionary fitness advantage of HLA-I heterozygosity.
Highlights
The large sequence diversity of the T cell receptors (TCRs) repertoire is a hallmark of the adaptive immune system, and varies markedly across individuals [1,2,3,4]
We first quantified TCR repertoire diversity by applying two measures widely used in repertoire and ecological studies—the number of unique CDR3β amino acid sequences (a.k.a. richness), and Shannon entropy, a diversity measure that is weighted by the abundance of each complementary determining region 3 (CDR3) [26]
Individuals with CMV (CMV+) exhibited a reduction in TCR repertoire diversity compared to those without (CMV-) (Fig. 1b-c). This reduction was most striking when using Shannon entropy (P < 0.0001, Wilcoxon test; Fig. 1b), consistent with prior work demonstrating that CMV alters the diversity, but not overall size of the CD8+ T cell response [29]. These data suggest that CMV diminishes TCR repertoire diversity, and are in line with a recent study demonstrating dramatic reduction of the antibody repertoire after measles infection [30]—highlighting the need for widespread and continuous vaccination against infectious disease
Summary
The large sequence diversity of the TCR repertoire is a hallmark of the adaptive immune system, and varies markedly across individuals [1,2,3,4]. MHC restriction is the cornerstone of T cell recognition [17], and prior reports have assessed the effect of the presence of specific MHC alleles on TCR V gene usage [18, 19] and repertoire sharing [9, 20]. These data, together with structural studies of the TCR-MHC interface [11, 21,22,23,24], have provided key insights into how the TCR binds MHC and peptide.
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