CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans.
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-gamma. 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.
Pulmonary Section, Medical Service, Department of Veterans Affairs Health System, Ann Arbor, MI 48105, USA. oster@umich.edu
John J
JJ
Osterholzer
Jeffrey L
JL
Curtis
Timothy
T
Polak
Theresa
T
Ames
Gwo-Hsiao
GH
Chen
Rod
R
McDonald
Gary B
GB
Huffnagle
Galen B
GB
Toews
D000818:Animals; D001980:Bronchi / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C515335:Ccr2 protein, mouse; D008024:Ligands; D012333:RNA, Messenger; D054390:Receptors, CCR2; D018664:Interleukin-12; D007371:Interferon-gamma