Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire.

Kai Gao,Xiu Qiu,Yashu Kuang,Lei Tian,Jinghua Wu,Yi Zhao,Xiao Liu,Jinhua Lu,Xiuqing Zhang,Lingyan Chen,Yuanwei Zhang,Ziyun Wan,Liya Lin

doi:10.3389/fimmu.2019.02064

Abstract

T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the “net” genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR β chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.

Highlights

Tcell immune surveillance is critical for the health of all jawed vertebrates
Our results showed that the frequencies of TRBV genes, but not the Immunol Globulin Heavy chain V (IGHV) genes, are significantly associated with major histocompatibility complex (MHC) alleles (Figure 1B, Supplementary Tables 4, 5)
Our results show that MHC polymorphism plays an important role in shaping umbilical cord blood (UCB) T cell receptors (TCRs) repertoires. 14.6% (7/48) of TRBV genes are significantly associated with nucleotide and/or amino acid variations of the MHC molecules

Summary

Introduction

Tcell immune surveillance is critical for the health of all jawed vertebrates. Most T cells express αβ TCRs and recognize peptides derived from digested proteins when presented at the cell surface in MHC molecules. How αβ TCR interacts with peptide-MHC (pMHC) has been a attractive field as it may contribute to developing strategies for manipulating T cell responses in many diseases including immunodeficiencies, tumor, autoimmune, and allergic diseases. Less variable regions CDR1 and CDR2 loop sequences are constant for each type of chain, and are referred to as “germline-derived.”. HLA genes are extremely polymorphic with more than 12,000 known alleles and MHC haplotypes are highly variable in different ethnic groups [5, 6]. In the dozens of structures of TCR-pMHC complexes that have been solved, CDR1 and CDR2 loops are shown to in contact with the conserved α-helical residues of the MHC molecules, and the highly variable CDR3 loops primarily interact with the peptide [7,8,9]

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