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MHC-II heterozygosity limits type 1 diabetes susceptibility through negative selection

Homozygous expression of MHC-II alleles that confer susceptibility to type 1 diabetes limits the efficiency of thymic negative selection and allows for CXCR6+ pathogenic clones to orchestrate the disease process. Expression of a second MHC-II allele decreases β-islet CD4+ T cell affinity, and limits CD8 cross-priming and diabetes risk without presenting the cognate MHC-II islet self-antigen.

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Fig. 1: Non-cognate negative selection eliminates CXCR6+ CD4+ T cell orchestrators of T1D.


  1. Huseby, E. S. & Teixeiro, E. The perception and response of T cells to a changing environment are based on the law of initial value. Sci. Signal. 15, eabj9842 (2022). A review article that highlights the role of self-peptide MHC recognition in T cell development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Todd, J. A. et al. A molecular basis for MHC class II-associated autoimmunity. Science 240, 1003–1009 (1988). This paper reports that MHC-II polymorphisms influence T1D susceptibility.

    Article  CAS  PubMed  Google Scholar 

  3. Hu, X. et al. Additive and interaction effects at three amino acid position in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 47, 898–905 (2015). This paper reports that homozygous expression of MHC-II susceptibility alleles increases T1D risk.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stadinski, B., Kappler, J. & Eisenbarth, G. S. Molecular targeting of islet autoantigens. Immunity 32, 446–456 (2010). A review article that presents the role of T cells and autoantigens in the T1D disease process.

    Article  CAS  PubMed  Google Scholar 

  5. Stadinski, B. D. et al. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat. Immunol. 17, 946–955 (2016). A paper that reports global changes in TCR CDR3 usage by self-reactive T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This is a summary of: Stadinski, B. D. et al. I-Ag7 β56/57 polymorphisms regulate non-cognate negative selection to CD4+ T cell orchestrators of type 1 diabetes. Nat. Immunol. (2023).

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MHC-II heterozygosity limits type 1 diabetes susceptibility through negative selection. Nat Immunol 24, 573–574 (2023).

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