Differential roles of CC chemokine ligand 2/monocyte chemotactic protein-1 and CCR2 in the development of T1 immunity.
CCR2 and its major ligand, chemokine ligand 2 (CCL2)/monocyte chemotactic protein-1, have been found to influence T1/T2 immune response polarization. Our objective was to directly compare the roles of CCR2 and CCL2 in T1/T2 immune response polarization using a model of pulmonary Cryptococcus neoformans infection. Either deletion of CCR2 or treatment of wild-type mice with CCL2 neutralizing Ab produced significant and comparable reductions in macrophage and T cell recruitment into the lungs following infection. Both CCL2 neutralization and CCR2 deficiency resulted in significantly diminished IFN-gamma production, and increased IL-4 and IL-5 production by lung leukocytes (T1 to T2 switch), but only CCR2 deficiency promoted pulmonary eotaxin production and eosinophilia. In the lung-associated lymph nodes (LALN), CCL2-neutralized mice developed Ag-specific IFN-gamma-producing cells, while CCR2 knockout mice did not. LALN from CCR2 knockout mice also had fewer MHCII(+)CD11c(+) and MHCII(+)CD11b(+) cells, and produced significantly less IL-12p70 and TNF-alpha when stimulated with heat-killed yeast than LALN from wild-type or CCL2-neutralized mice, consistent with a defect in APC trafficking in CCR2 knockout mice. Neutralization of CCL2 in CCR2 knockout mice did not alter immune response development, demonstrating that the high levels of CCL2 in these mice did not play a role in T2 polarization. Therefore, CCR2 (but not CCL2) is required for afferent T1 development in the lymph nodes. In the absence of CCL2, T1 cells polarize in the LALN, but do not traffic from the lymph nodes to the lungs, resulting in a pulmonary T2 response.
Traynor
Tim R
TR
Pulmonary Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Herring
Amy C
AC
Dorf
Martin E
ME
Kuziel
William A
WA
Toews
Galen B
GB
Huffnagle
Gary B
GB
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D003453:Cryptococcosis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D006098:Granulocytes / Q000276:immunology; D008168:Lung / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000276:immunology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000906:Antibodies; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine