Research ArticleAUTOIMMUNITY

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

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Science Immunology  23 Mar 2018:
Vol. 3, Issue 21, eaam6533
DOI: 10.1126/sciimmunol.aam6533

Infiltration inhibition

Type 1 diabetes (T1D) is associated with the infiltration of islet-specific autoreactive cytotoxic CD8+ T cells (CTLs) in pancreatic islets, which leads to islet destruction and loss of insulin production. Most of the CTLs in islets are non–islet-specific, and their contribution to T1D is not well understood. Christoffersson et al. observed that the accumulation of these “bystander” CTLs is associated with decreased activation and proliferation of islet-specific CTLs. The abundance of non–islet-specific CTLs in islets reduced the accessibility of islet-specific CTLs to autoantigens, which led to a state of unresponsiveness. A similar form of nonspecific suppression by CTLs was observed in a viral meningitis model. Together, these results reveal an immune-regulatory role for nonautoreactive CTLs.


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.

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