Abstract
Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B, ZBTB24, RAG1, DCLRE1C, and JAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients with DNMT3B and ZBTB24 mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.
Highlights
Inborn errors of immunity (IEI) or primary immunodeficiency diseases (PIDs) constitute a group of highly heterogeneous genetic disorders caused by defects in the immuneOne Sentence Summary: Immune repertoire in DNA repair and methylation defects.Mingyan Fang, Zheng Su, and Hassan Abolhassani contributed to this work.The diversity of antigen receptor repertoires is generated by recombination of the variable (V), diversity (D), and1 3 Vol.:(0123456789)Journal of Clinical Immunology joining (J) gene segments
Variable T cell receptor (TCR) repertoire characteristics in different disease groups were revealed based on genomic data comparison with healthy donors
The finding provides clues to address the function of Ataxia-telangiectasia mutated kinase (ATM), DNA methyltransferase 3B (DNMT3B), and zinc finger and BTB domain containing 24 (ZBTB24) proteins during V(D)J recombination
Summary
Inborn errors of immunity (IEI) or primary immunodeficiency diseases (PIDs) constitute a group of highly heterogeneous genetic disorders caused by defects in the immuneOne Sentence Summary: Immune repertoire in DNA repair and methylation defects.Mingyan Fang, Zheng Su, and Hassan Abolhassani contributed to this work.The diversity of antigen receptor repertoires is generated by recombination of the variable (V), diversity (D), and1 3 Vol.:(0123456789)Journal of Clinical Immunology joining (J) gene segments. One Sentence Summary: Immune repertoire in DNA repair and methylation defects. The diversity of antigen receptor repertoires is generated by recombination of the variable (V), diversity (D), and. The diversity is further augmented by junctional diversity (non-templated (N) nucleotide additions in the V-D and D-J junctions inserted by terminal deoxynucleotidyl transferase (TdT) and random deletion of nucleotides at the recombining edges as a consequence of asymmetric hairpin opening by ARTEMIS) [3,4,5]. The productive T cell receptor (TCR) repertoire further undergoes a selection process in the thymus and subsequently through interaction with antigens. During V(D)J recombination, DNA double-strand breaks (DSBs) near the V, D, and J coding gene segments and recombination signal sequences [6] are introduced by the recombination activating gene (RAG1 and RAG2) complex, and mutations in these two genes can lead to severe combined immunodeficiency (SCID) [7]
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