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* Pulmonary Division, Departments of Internal Medicine and
Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109;
Department of Pathology, Harvard Medical School, Boston, MA 02115; and
Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712
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-
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--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-
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.
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