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The Journal of Immunology, 1999, 162: 2511-2520.
Copyright © 1999 by The American Association of Immunologists

Islet-Specific Th1, But Not Th2, Cells Secrete Multiple Chemokines and Promote Rapid Induction of Autoimmune Diabetes1

Linda M. Bradley2,*, Valérie C. Asensio{dagger}, Li-Karine Schioetz*, Judith Harbertson*, Troy Krahl*, Gail Patstone*, Nigel Woolf{ddagger}, Iain L. Campbell{dagger} and Nora Sarvetnick*

Departments of * Immunology and {dagger} Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037; and {ddagger} Department of Surgery, University of California at San Diego, La Jolla, CA 92037

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet ß-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1{alpha}, whereas both subsets produced macrophage inflammatory protein-1ß. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing ß-cells are protected or destroyed.




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