Suppression of diabetes by accumulation of non-islet-specific CD8 + effector T cells in pancreatic islets

Sci Immunol. 2018 Mar 23;3(21):eaam6533. doi: 10.1126/sciimmunol.aam6533.

Abstract

The inflammatory lesion at the pancreatic islet in type 1 diabetes (T1D) contains a heterogeneous infiltrate of T cells. In human and mouse studies, a large majority (98 to 99%) of the cytotoxic CD8+ T cells (CTLs) within islets are not specific to any islet antigen and are thought to passively add to tissue damage. We show by intravital confocal microscopy the opposite, immune-regulatory function of this cohort of CTLs. Diabetes did not develop in mice with islets showing high levels of infiltration of non-islet-specific CTLs not recognizing local antigens. Accumulation of such CTLs resulted in lower activation and proliferation of islet-specific CTLs, leading them to enter a state of unresponsiveness due to limited access to antigens at the inflammatory lesion. This nonspecific suppression by nonautoreactive CTLs was recapitulated in a model of viral meningitis, may explain viral interference in autoimmunity, and provides insight into the regulation of organ-specific autoimmune responses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens / immunology
  • Autoimmunity
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Islets of Langerhans / immunology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Antigens