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MHC-dependent desensitization of intrinsic anti-self reactivity

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Abstract

The survival of naïve T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naïve T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naïve B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance.

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Acknowledgments

The authors wish to thank Susan Fosmire, Dr. Angela Pierce, Dr. Ashley Frazer-Abel, and Dr. John Wojcieszyn for assistance with experiments, Dr. Tadashi Yamamoto for the Tob1 knockout mice, and Drs. Anne Avery, Kristin Hogquist, and Stephen Jameson for review of the manuscript and helpful discussions. This work was supported by a grant from The Cancer League of Colorado, Inc., by grants R21DK63410, P30CA46934, R01DK58722, and PO1HD38129 from the National Institutes of Health, by a grant from the Monfort Family Foundation, and by discretionary funds from the Integrated Department of Immunology and the University of Colorado Cancer Center. ARL was the recipient of a post-doctoral fellowship from the University of Colorado Cancer Center.

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Author notes

  1. Angela R. Lamerato-Kozicki

    Present address: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA

  2. Monika Baier

    Present address: Clinical & Regulatory Affairs/Biometrics Department Biostatistician, Novartis Pharma GmbH, Roonstrasse 25, 90429, Nuernberg, Germany

Authors and Affiliations

  1. University of Colorado Cancer Center, Aurora, CO, USA

    Cristan M. Jubala, Angela R. Lamerato-Kozicki, Lori A. Gardner, Karen M. Helm, Jerome Schaack, Donald Bellgrau & Jaime F. Modiano

  2. Integrated Department of Immunology, University of Colorado, Denver, CO, USA

    Angela R. Lamerato-Kozicki, Michelle Borakove, Julie Lang, David Coffey, Donald Bellgrau & Jaime F. Modiano

  3. Department of Microbiology, University of Colorado, Denver, CO, USA

    Jerome Schaack

  4. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

    Monika Baier & Gary R. Cutter

  5. Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, 455 VMC MMC6194, 1365 Gortner Avenue, St. Paul, MN, 55108, USA

    Jaime F. Modiano

  6. Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson St. K503, Denver, CO, 80206, USA

    Donald Bellgrau

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  1. Cristan M. Jubala
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Correspondence to Donald Bellgrau or Jaime F. Modiano.

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Donald Bellgrau and Jaime F. Modiano contributed equally to this work.

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Jubala, C.M., Lamerato-Kozicki, A.R., Borakove, M. et al. MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother 58, 171–185 (2009). https://doi.org/10.1007/s00262-008-0535-0

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