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CCR2 Expression Determines T1 Versus T2 Polarization During Pulmonary Cryptococcus neoformans Infection¹

Tim R. Traynor^*, William A. Kuziel, Galen B. Toews^* and Gary B. Huffnagle^2,*

^* Pulmonary Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and Department of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712

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-, 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.