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CCR2 Mediates Conventional Dendritic Cell Recruitment and the Formation of Bronchovascular Mononuclear Cell Infiltrates in the Lungs of Mice Infected with Cryptococcus neoformans^1,2

John J. Osterholzer^3,*,, Jeffrey L. Curtis^*,, Timothy Polak, Theresa Ames, Gwo-Hsiao Chen, Rod McDonald, Gary B. Huffnagle and Galen B. Toews^*,

^* Pulmonary Section, Medical Service, Department of Veterans Affairs Health System, and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48105

Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans requires the development of T1-type immunity. CCR2-deficient mice infected with C. neoformans develop a non-protective T2 immune response and persistent infection. The mechanisms responsible for this aberrant response are unknown. The objective of this study was to define the number, phenotype, and microanatomic location of dendritic cells (DC) residing within the lung of CCR2^+/+ or CCR2^–/– mice throughout a time course following infection with C. neoformans. Results demonstrate the CCR2-mediated recruitment of conventional DC expressing modest amounts of costimulatory molecules. DC recruitment was preceded by the up-regulation in the lung of the CCR2 ligands CCL2 and CCL7. Colocalization of numerous DC and CD4⁺ T cells within bronchovascular infiltrates coincided with increased expression of IL-12 and IFN-. By contrast, in the absence of CCR2, DC recruitment was markedly impaired, bronchovascular infiltrates were diminished, and mice developed features of T2 responses, including bronchovascular collagen deposition and IL-4 production. Our results demonstrate that CCR2 is required for the recruitment of large numbers of conventional DC to bronchovascular infiltrates in mice mounting a T1 immune response against a fungal pathogen. These findings shed new insight into the mechanism(s) by which DC recruitment alters T cell polarization in response to an infectious challenge within the lung.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Merit Review Awards (to G.B.T. and J.L.C.) and a Career Development Award-2 (to J.J.O.) from the Biomedical Laboratory Research and Development Service, Department of Veterans Affairs, and by National Institutes of Health Grants R01-HL065912 (to G.B.H.), R01-AI059201 (to G.B.H.), R01-HL051082 (to G.B.T.), and T32-AI07413 (to J.J.O.).

² Portions of this work have been presented previously at the International Conference of the American Thoracic Society, San Diego, CA, May 22, 2005 and May 22, 2006 and have been published in abstract form (Proc. Am. Thorac. Soc. (2);A364, May 2005 and Proc. Am. Thorac. Soc. (3):A346, 2006) and as an oral presentation at the Keystone Symposium: Determinants of Host Resistance, Susceptibility or Immunopathology to Pathogens: Integrating Knowledge from Experimental Models to Human Disease, Keystone, CO, January 2006.

³ Address correspondence and reprint requests to Dr. John J. Osterholzer, Pulmonary and Critical Care Medicine Section (111G), Department of Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105. E-mail address: oster{at}umich.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; BAL, bronchoalveolar lavage; cDC, conventional dendritic cell; mDC, myeloid dendritic cell; i.t., intratracheal.