Assistant Professor UMass Chan Med. Sch., Massachusetts, United States
Disclosure(s):
Brian Stadinski, PhD: No financial relationships to disclose
Introduction/Rationale: T cell-mediated autoimmune diseases, such as type-1 diabetes (T1D), occur when breaks in tolerance mechanisms allow lymphocytes to target healthy tissue. The strongest genetic linkage for T1D susceptibility results from the 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.
Methods: NOD mice were generated carrying I-Ag7 β-chain 56/57 with a Pro-Asp, I-Ag7-PD, sequence, as well as I-Ag7-deficient, I-Ag7-null, mice. We tracked T1D development and characterized islet infiltrates from MHCII homozygous, hemizygous and heterozygous NOD mice. Additionally, we probed the thymic development and peripheral expansion of the β-islet specific T cell repertoire utilizing tetramers for known MHCII and MHCI epitopes.
Results: MHCII homozygous, I-Ag7-WT/WT, and hemizygous, I-Ag7-WT/null, developed T1D, while dominant protection occurred in heterozygous I-Ag7-PD/WT NOD mice. Islet infiltrates of protected mice showed reduced CXCR6+ CD4 T cells and a loss in CD8 T cells. Thymic analysis showed a loss in high-affinity β-islet specific cells and correlated with decreased CD4SP development beginning at the DP stage. Surprisingly, protective I-Ag7-PD molecule are less efficient at presenting cognate islet autoantigens, do not prime β-islet specific CD4 T cells in vivo nor elicit increased allogeneic responses. However, I-Ag7-PD activates increasing numbers of DP thymocytes compared to I-Ag7-WT. Expansions of islet-specific CD4 T cells occur in all I-Ag7-WT bearing mice, yet only CXCR6+ cells emerge in T1D susceptible mice. Adoptive transfer of CXCR6+ CD4 T cells reveals an ability to induce cross priming islet-specific CD8 T cells and drive T1D development.
Conclusion: These data argue that pathogenic islet-specific CD4 T cell clones can be subject to negative selection following recognition of self-peptide/I-Ag7-PD ligands that are distinct from the cognate autoantigen.
