Recruitment and activation of macrophages by pathogenic CD4 T cells in type 1 diabetes: evidence for involvement of CCR8 and CCL1.
Adoptive transfer of diabetogenic CD4 Th1 T cell clones into young NOD or NOD.scid recipients rapidly induces onset of diabetes and also provides a system for analysis of the pancreatic infiltrate. Although many reports have suggested a role for macrophages in the inflammatory response, there has been little direct characterization of macrophage activity in the pancreas. We showed previously that after migration to the pancreas, diabetogenic CD4 T cell clones produce a variety of inflammatory cytokines and chemokines, resulting in the recruitment of macrophages. In this study, we investigated mechanisms by which macrophages are recruited and activated by T cells. Analysis of infiltrating cells after adoptive transfer by the diabetogenic T cell clone BDC-2.5 indicates that large numbers of cells staining for both F4/80 and CD11b are recruited into the pancreas where they are activated to make IL-1beta, TNF-alpha, and NO, and express the chemokine receptors CCR5, CXCR3, and CCR8. Diabetogenic CD4 T cell clones produce several inflammatory chemokines in vitro, but after adoptive transfer we found that the only chemokine that could be detected ex vivo was CCL1. These results provide the first evidence that CCR8/CCL1 interaction may play a role in type 1 diabetes through macrophage recruitment and activation.
Cantor
Joseph
J
Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80206, USA.
Haskins
Kathryn
K
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054402:Chemokine CCL1 / Q000378:metabolism*; D002633:Chemotaxis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000096:biosynthesis; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D054401:Receptors, CCR8 / Q000378:metabolism*
D039481:CD11b Antigen; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D054401:Receptors, CCR8; D009569:Nitric Oxide