The role of monocyte chemotactic protein-1 (MCP-1) in the recruitment of monocytes and CD4+ T cells during a pulmonary Cryptococcus neoformans infection.
Cryptococcus neoformans is acquired via the respiratory tract and is the leading cause of fatal mycosis in AIDS. Development of a T cell-mediated pulmonary inflammatory response is critical for clearance of this pathogen; however, the chemotactic factors that mediate inflammatory cell recruitment into the lungs have not been identified. In the present study, the bronchoalveolar lavage (BAL) fluid levels of the C-C chemokine monocyte chemotactic protein-1 (MCP-1) and the recruitment of inflammatory cells both increased following pulmonary infection with C. neoformans. The kinetics of MCP-1 production in the lungs correlated most closely with the recruitment of CD4+ T cells and monocytes/macrophages. Administration of neutralizing anti-MCP-1 Abs in vivo reduced the BAL fluid levels of MCP-1, decreased the recruitment of both macrophages (> 95%) and CD4+ T cells (76 +/- 9%), and inhibited cryptococcal clearance. Although no in vitro neutrophil or B cell chemotactic activity has been reported for MCP-1, recruitment of these leukocytes was also decreased in anti-MCP-1-treated mice (most likely an indirect effect of reducing the number of CD4+ T cells and macrophages). Neutralization of MCP-1 also resulted in decreased BAL fluid levels of TNF-alpha and IL-6. This is the first demonstration of a role for MCP-1 in clearance of an infection, and provides direct evidence that MCP-1 plays a critical role in the T cell-dependent immune response to C. neoformans.
Huffnagle
G B
GB
Internal Medicine-Pulmonary and Critical Care Medicine Division, University of Michigan Medical Center, Ann Arbor 48109, USA.
Strieter
R M
RM
Standiford
T J
TJ
McDonald
R A
RA
Burdick
M D
MD
Kunkel
S L
SL
Toews
G B
GB
D000818:Animals; D018893:Bronchoalveolar Lavage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018932:Chemokine CCL2 / Q000276:immunology*; D002633:Chemotaxis; D003453:Cryptococcosis / Q000276:immunology* / Q000473:pathology; D005260:Female; D007111:Immunity, Cellular; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009000:Monocytes / Q000276:immunology* / Q000473:pathology
D018932:Chemokine CCL2