For the large array of self-peptide/MHC class II (pMHC-II) complexes displayed in the body, it is unclear whether CD4+ T cell tolerance must be imparted for each individual complex or whether pMHC-II–nonspecific bystander mechanisms are sufficient to confer tolerance by acting broadly on T cells reactive to multiple self-pMHC-II ligands. Here, via reconstitution of T cell–deficient mice, we demonstrate that altered T cell selection on a single prostate-specific self-pMHC-II ligand renders recipient mice susceptible to prostate-specific T cell infiltration. Mechanistically, this self-pMHC-II complex is required for directing antigen-specific cells into the Foxp3+ regulatory T cell lineage but does not induce clonal deletion to a measurable extent. Thus, our data demonstrate that polyclonal T reg cells are unable to functionally compensate for a breach in tolerance to a single self-pMHC-II complex in this setting, revealing vulnerabilities in antigen-nonspecific bystander mechanisms of immune tolerance.
Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration
Disclosures: D.C. Gilmore reported grants from National Institute of Cancer and grants from National Institute of Allergy and Infectious Disease during the conduct of the study and personal fees from Compass Therapeutics and personal fees from TCR2 Therapeutics outside the submitted work. J.D. Leonard reported personal fees from 3T Biosciences outside the submitted work. No other disclosures were reported.
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David E.J. Klawon, Dana C. Gilmore, John D. Leonard, Christine H. Miller, Jaime L. Chao, Matthew T. Walker, Ryan K. Duncombe, Kenneth S. Tung, Erin J. Adams, Peter A. Savage; Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration. J Exp Med 7 June 2021; 218 (6): e20200701. doi: https://doi.org/10.1084/jem.20200701
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