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CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms

Abstract

The inhibitory immunoregulatory receptor CTLA-4 is critical in maintaining self-tolerance, but the mechanisms of its actions have remained controversial. Here we examined the antigen specificity of tissue-infiltrating CD4+ T cells in Ctla4−/− mice. After adoptive transfer, T cells isolated from tissues of Ctla4−/− mice showed T cell antigen receptor (TCR)-dependent accumulation in the tissues from which they were derived, which suggested reactivity to tissue-specific antigens. We identified the pancreas-specific enzyme PDIA2 as an autoantigen in Ctla4−/− mice. CTLA-4 expressed either on PDIA2-specific effector cells or on regulatory T cells was sufficient to control tissue destruction mediated by PDIA2-specific T cells. Our results demonstrate that both cell-intrinsic and non–cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen.

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Figure 1: DOβCtla4−/− mice show spontaneous T cell activation and multiorgan infiltration.
Figure 2: Tissue-infiltrating T cells from DOβCtla4−/− mice cause tissue-specific inflammation.
Figure 3: TCRs derived from pancreas-infiltrating T cells confer selective pancreatic accumulation.
Figure 4: PDIA2 is an autoantigen in Ctla4−/− mice.
Figure 5: Isolation of PDIA2-specific TCRs from TCRα library.
Figure 6: PDIA2-specific Ctla4−/− T cells infiltrate the pancreas.
Figure 7: CTLA-4-sufficient Treg cells inhibit pancreatitis induced by Ctla4−/− PDIA2-specific T cells.

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Acknowledgements

We thank W. Sha (University of California Berkeley) for the MSCV IRES-Thy-1.1 retrovirus; M. Iwashima (Medical College of Georgia) for pKS-NFAT-GFP; and M. Hurchla, M. Sandau and B. Schraml for critically reading the manuscript. Supported by the Howard Hughes Medical Institute (K.M.M.) and the US National Institutes of Health (AI031238 and AI070489 to K.M.M.).

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W.I. designed experiments, did research, analyzed and interpreted results and wrote the manuscript; M.K. did TCRα cDNA cloning; K.M.N. and H.M.L. helped generate the TCRα library; A.S. and E.R.U. provided beta cells and contributed to the hybridoma assay; T.L.M. helped sort cells and contributed to the generation of the TCRα library; and K.M.M. directed the study, analyzed and interpreted results and wrote the manuscript.

Corresponding author

Correspondence to Kenneth M Murphy.

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Ise, W., Kohyama, M., Nutsch, K. et al. CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 11, 129–135 (2010). https://doi.org/10.1038/ni.1835

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