Differences in F pocket impact on HLA I genetic associations with autoimmune diabetes

Front Immunol. 2024 Mar 25:15:1342335. doi: 10.3389/fimmu.2024.1342335. eCollection 2024.

Abstract

Introduction: Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8+ T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8+ T cells that destroy insulin-producing pancreatic β cells. Some HLA I alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles).

Methods: Here, we compared the T1D-predisposing and T1D-protective allotypes concerning peptide binding, maturation, localization and surface expression and correlated it with their sequences and energetic profiles using experimental and computational methods.

Results: T1D-predisposing allotypes had more peptide-bound forms and higher plasma membrane levels than T1D-protective allotypes. This was related to the fact that position 116 within the F pocket was more conserved and made more optimal contacts with the neighboring residues in T1D-predisposing allotypes than in protective allotypes.

Conclusion: Our work uncovers that specific polymorphisms in HLA I molecules potentially influence their susceptibility to T1D.

Keywords: HLA class I; antigen presentation; autoimmune diabetes; inflammation; peptide binding; polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Diabetes Mellitus, Type 1*
  • HLA Antigens / metabolism
  • Histocompatibility Antigens / metabolism
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Peptides / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Peptides
  • Histocompatibility Antigens Class II
  • HLA Antigens
  • Histocompatibility Antigens

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work was supported by the National Natural Science Foundation of China grants (81870536, 81700691), a Personal Fellowship (Grant No. 87679215) and a Start-Up Budget (Grant No. 82668428), all to MG. The Second Affiliated Hospital of Xi’an Jiaotong University supported the publication of this study.