MHC-II polymorphisms regulate non-cognate negative selection OF CD4 T cell orchestrators of type-1 diabetes 4733
Year: 2025
Type: article
Abstract: Description T cell-mediated autoimmune diseases, such as type-1 diabetes (T1D), occur when breaks in tolerance allow lymphocytes to target healthy tissue. Genetic susceptibility to T1D relies on homozygous expression of MHC-II alleles carrying particular β-chain polymorphisms. Why heterozygous expression of these MHC-II alleles does not confer a similar predisposition remains unresolved. To address how MHC-II alleles influence T1D susceptibility, we mutated the I-Ag7 β56/57 polymorphic residues, His-Ser, to the canonical Pro-Asp, generating non-obese diabetic (NOD) mice that express I-Ag7-PD. While I-Ag7-WT/WT homozygous mice develop T1D, heterozygous I-Ag7-PD/WT mice are T1D-resistant, exhibit a lack of islet-specific CD8 T cell cross-priming, and forego islet-specific CD4 T cell CXCR6+ subset differentiation. Adoptive transfer of the CXCR6+ CD4 T cell populations from NOD mice reveals an ability to induce islet-specific CD8 T cell activation and drive T1D. Additionally, heterozygous expression of the protective I-Ag7-PD allele induces significant thymic deletion of the I-Ag7-WT restricted T cell repertoire. Surprisingly, negative selection of high-affinity islet-specific CD4 T cells occurs despite I-Ag7-PD having a reduced ability to present islet-specific CD4 T cell antigens. These data argue that negative selection of diabetogenic CD4 T cells by disease protective MHC-II molecules occurs through ligands that are distinct from the cognate autoantigen. Topic Categories Basic Autoimmunity (BA)
Source: The Journal of Immunology
Author: Brian Stadinski
Institution: University of Massachusetts Chan Medical School
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416447449
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