Genetic and environmental determinants of human TCR repertoire diversity
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Genetic and environmental determinants of human TCR repertoire diversity Chirag Krishna1,2†, Diego Chowell2,4†, Mithat Gönen3, Yuval Elhanati3,4* and Timothy A. Chan2,4,5,6,7*
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. Keywords: Major histocompatibility complex, Heterozygote advantage, T cell receptor repertoire, Infection, Aging, Immunogenetics
Background The large sequence diversity of the TCR repertoire is a hallmark of the adaptive immune system, and varies markedly across individuals [1–4]. This diversity, estimated to exceed 106 sequences in humans [5–7], is shaped by stochastic [8] and genetic [9] effects in conjunction with continuous immunological challenges throughout life [9]. In the thymus, VDJ recombination facilitates random rearrangement of the complementary determining region 3 (CDR3) within the TCR α and β loci, followed by random nucleotide insertion and deletions at junction sites [10]. The CDR3 regions of the TCR are primarily responsible for interacting with the peptide presented by MHC [11], with the potential
* Correspondence: [email protected]; [email protected] † Chirag Krishna and Diego Chowell contributed equally to this work. 3 Department of Epidemiology and Biostatistics, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Full list of author information is available at the end of the article
diversity of CDR3β exceeding that of CDR3α [12]. Whether a particular TCR joins the periphery depends on its behavior during thymic selection, in which TCRs interact with both self peptide and MHC [13, 14]. TCRs that fail to bind to peptide-MHC complexes and those that bind too strongly are eliminated [15, 16]. Those TCRs that survive thymic selection are responsible for mounting productive immune responses through continuous interaction with self and foreign peptides bound to MHC molecules. TCR diversity can determine how efficiently one rejects pathogens such as viruses, and potentially cancer cells. Accordingly, considerable effort has been devoted to understanding how MHC gene
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