CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection.
Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans requires the development of T1-type immunity. The objective of this study was to determine the role of CCR2 in leukocyte recruitment and development of T1-type cell-mediated immunity during pulmonary C. neoformans infection. Intratracheal inoculation of C. neoformans into CCR2 knockout (CCR2-/-) mice produced a prolonged pulmonary infection (5000-fold CFU at 6 wk compared with CCR2+/+ mice) and significant dissemination to the spleen and brain (160- and 800-fold greater). In addition, CCR2 deficiency resulted in significantly reduced recruitment of macrophages (weeks 1-3) and CD8+ T cells (weeks 1-2) into the lungs. The immune response in CCR2-/- mice was characterized by chronic pulmonary eosinophilia, crystal deposition in the lungs, pulmonary leukocyte production of IL-4 and IL-5 but not IFN-gamma, lack of anticryptococcal delayed-type hypersensitivity, and high levels of serum IgE. These results demonstrate that expression of CCR2 is required for the development of a T1-type response to C. neoformans infection and lack of CCR2 results in a switch to a T2-type response. Thus, CCR2 plays a critical role in promoting the development of T1- over T2-type immune responses in the lung following cryptococcus infection.
Traynor
T R
TR
Pulmonary Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Kuziel
W A
WA
Toews
G B
GB
Huffnagle
G B
GB
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007111:Immunity, Cellular; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine