MHC antigen induction by interferon γ on cultured mouse pancreatic β cells and macrophages. Genetic analysis of strain differences and discovery of an 'occult' class I-like antigen in NOD/Lt mice

E. H. Leiter, G. J. Christianson, D. V. Serreze, A. T. Ting, S. M. Worthen

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37 Scopus citations


This study provides a basis for understanding the wide variations reported in the literature in IFN-γ inducibility of class II MHC antigen on murine β cells. Inducibility is not an intrinsic property of all mouse β cells, but instead depends upon strain- (and tissue-) specific response modifying factors. This was demonstrated by comparison of constitutive and IFN-γ-induced class I and class II MHC gene products on cultured islet cell monolayers. Islet cultures were established from autoimmune diabetes-prone NOD/Lt mice, diabetes-resistant NON/Lt and CBA/J mice, as well as F1 hybrids between these latter two strains and NOD/Lt. Cultures of peritoneal macrophages (Mφ) from each strain were established as controls. After 3 wk of culture (with incubation in the presence or absence of IFN-γ during the last 6 d), constitutive expression as well as IFN-γ induction of class I MHC antigen expression was demonstrated on NOD/Lt and NON/Lt islet cells by antibody plus complement-mediated cytotoxicity. Although CBA/J islets and Mφ did not maintain constitutive class I or class II antigen expression in culture in the absence of IFN-γ, class I H-2K(k) antigen was IFN-γ inducible. Whereas IFN-γ-induced class II I-A(k) antigen on CBA/J Mφ, it failed to induce this antigen on CBA/J islets. In contrast, I-A antigens were IFN-γ inducible on NOD/Lt and NON/Lt islets and Mφ. In (CBA X NOD)F1 hybrids, loss of IFN-γ inducibility of the I-A(NOD) product established that suppression was mediated by a trans-acting factor from the CBA/J genome. In the course of these studies, IFN-γ inducibility of a crossreactive occult class I-like antigen on both NOD/Lt islet cell and Mφ cultures was unexpectedly detected when mAb 28-13-3 (public specificity 39, reactive with H-2K(b,f)) was used as a negative control. Although not detectable by cytofluorographic analysis of freshly isolated NOD/Lt splenic leukocytes, occult antigen could be induced on NOD/Lt peritoneal macrophages (Mφ) cultured for 3 d in IFN-γ. Time course of induction showed the occult antigen to be distinct from NOD/Lt class I and II gene products. In both islet cell and Mφ cultures established from (CBA X NOD)F1 hybrids, trans-suppressive factor(s) from the CBA/J genome not only suppressed IFN-γ-induced expression of I-A(NOD), but additionally suppressed occult antigen induction. Backcross of F1 to both parental strains indicated that the occult locus was on Chr 17, tightly linked to MHC. Polygenic control of IFN-γ responsiveness was indicated, and the possibility that the inducible antigen may be encoded by a Qa-like gene was discussed. Diabetogenesis in NOD mice entails a T lymphocyte-mediated destruction of pancreatic β-cells. Although insulitis is an histopathologic feature of diabetogenesis detected shortly after weaning, erosion of pancreatic insulin content is not observed until several months thereafter. Insulin content does not decline gradually, but appears to drop precipitously. Lymphokines such as IFN-γ from infiltrating cells could induce β cell expression of surface proteins, including MHC antigens, that may in turn activate cytotoxic effector cells. We have demonstrated the potential for such an interaction in vitro. NOD/Lt T cells primed in vivo to splenocytes from a NOD.NON-H-2Kb congenic stock proliferated in vitro in response to IFN-γ-treated NOD islets but not untreated NOD islets. This model system suggests the interesting possibility that accumulation of IFN-γ around NOD β cells in situ could trigger activation of NOD T cells via induction of occult antigen on β cell surfaces.

Original languageEnglish (US)
Pages (from-to)1243-1262
Number of pages20
JournalJournal of Experimental Medicine
Issue number4
StatePublished - 1989

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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