Constrained self-antigen presentation in thymus underlies initiation of tissue-targeted autoimmunity

ABSTRACT: Presentation of tissue-restricted antigens (TRA) in the thymus is essentialfor establishing self-tolerancethrough elimination of autoreactive Tcells.It remains unclear why certain self T cells can bypassthymic selectionand become driversoftissue-specific autoimmunity. Herewe assessedthymic TRA presented by a major histocompatibility class II molecule (MHC-II) that confers genetic propensity to develop type 1 diabetes. This analysisestablished the thymic peptidome containing self-peptidesderivedfrom variousperipheral tissues,butalso revealed a disparity in the MHC-II epitoperepertoirebetween thymus and the target site of autoimmunity, the pancreatic islets.The thymic repertoire consistedof canonicalMHC-IIepitopes capable of enforcing central tolerance but lacked presentation of uniqueepitopes derived from unconventionalself-proteinprocessing orneoepitopes formed by post-translational modifications. Suchepitopes were noteworthily generatedin the isletsvia a tissue-intrinsic mechanism, crinophagy, and were recognized by CD4 T cells escaping central tolerance.These findings supportthat central tolerance mechanisms are effective but incomplete, as tissue-characteristic handling of self-antigens may broaden the peripheralrepertoire thatextends beyond the scope of thymic selection.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet, Professional Antigen Presenting Cell, Pancreatic Islet Cell, Insulin Catabolic Process, Thymus

SUBMITTER: Cheryl Lichti  

LAB HEAD: Emil Unanue

PROVIDER: PXD030999 | Pride | 2024-08-22

REPOSITORIES: Pride