Autoreactive cytotoxic T lymphocytes acquire higher expression of cytotoxic effector markers in the islets of NOD mice after priming in pancreatic lymph nodes

Am J Pathol. 2011 Jun;178(6):2716-25. doi: 10.1016/j.ajpath.2011.02.015.


Cytotoxic T lymphocytes (CTLs) that cause type 1 diabetes are activated in draining lymph nodes and become concentrated as fully active CTLs in inflamed pancreatic islets. It is unclear whether CTL function is driven by signals received in the lymph node or also in the inflamed tissue. We studied whether the development of cytotoxicity requires further activation in islets. Autoreactive CTLs found in the islets of diabetes-prone NOD mice had acquired much higher expression of the cytotoxic effector markers granzyme B, interferon γ, and CD107a than had those in the pancreatic lymph node (PLN). Increased expression seemed to result from stimulation in the islet itself. T cells held up from migrating from the PLN by administration of the sphingosine-1-phosphate agonist FTY720 did not increase expression of cytotoxic molecules in the PLN. Stimulation did not require antigen presentation or cytokine secretion by the target β cells because it was not affected by the absence of class I major histocompatibility complex expression or by the overexpression of suppressor of cytokine signaling-1. Activation of CD40-expressing cells stimulated increased CTL function and β-cell destruction, suggesting that signals derived from CD40-expressing cells promote the acquisition of cytotoxicity in the islet environment. These data provide in vivo evidence that stimulation of cytotoxic effector molecule expression occurs in inflamed islets and is independent of β cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Biomarkers / metabolism
  • Cell Proliferation
  • Cross-Priming / immunology*
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / immunology
  • Inflammation / complications
  • Inflammation / immunology
  • Inflammation / pathology
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology*
  • Lymph Nodes / immunology*
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred NOD
  • Rats
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology


  • Biomarkers
  • Cytokines