Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cell s are associated with pathogenesis leading to destruction of islet beta-cel ls and disease onset. Lymphocyte extravasation from blood into tissue is re gulated 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 tran sgenic 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 induce d diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by t he capacity to synthesize several chemokines that included lymphotactin, mo nocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory prote in-1 alpha, whereas both subsets produced macrophage inflammatory protein-1 beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytoki ne-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polari zation of chemokine expression by Th1 vs Th2 cells, which, within the micro environment of the pancreas, accounts for distinctive inflammatory infiltra tes that determine whether insulin-producing beta-cells are protected or de stroyed.