title: The role of macrophage inflammatory protein-1 alpha/CCL3 in regulation of T cell-mediated immunity to Cryptococcus neoformans infection.
abstract: Macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) is a CC chemokine required for optimal recruitment of leukocytes in response to cryptococcal Ags. MIP-1alpha is expressed in the lungs by day 6 post Cryptococcus neoformans infection and could play a role in the development of cell-mediated immunity. To address this possibility, wild-type (MIP-1alpha(+/+)) mice and MIP-1alpha knockout (MIP-1alpha(-/-)) mice were infected intratracheally with a highly virulent strain of C. neoformans (145A). MIP-1alpha message was detected in the lungs on days 3, 7, and 14 in MIP-1alpha(+/+) mice, but it was undetectable in MIP-1alpha(-/-) mice. On day 16, MIP-1alpha(-/-) mice had a 7-fold increase in C. neoformans burden in the lungs, but no decrease in pulmonary leukocyte recruitment. MIP-1alpha(+/+) and MIP-1alpha(-/-) mice had similar numbers of recruited lymphocytes and monocytes/macrophages. Notably, MIP-1alpha(-/-) mice had a significantly greater number of eosinophils. MIP-1alpha(-/-) mice had extremely high levels of serum IgE. This switch of immune response to a T(2) phenotype was associated with enhanced IL-4 and IL-13 expression in the lungs of MIP-1alpha(-/-) mice compared with MIP-1alpha (+/+) mice. Progression of pulmonary cryptococcosis in the presence of nonprotective T(2) immunity resulted in profound lung damage in MIP-1alpha(-/-) mice (eosinophilic crystal deposition, destruction of lung parenchyma, and pulmonary hemorrhage). Twelve-week survival was dramatically decreased in MIP-1alpha(-/-) mice. These studies, together with our previous studies, demonstrate that MIP-1alpha plays a role in both the afferent (T(1)/T(2) development) and efferent (T(1)-mediated leukocyte recruitment) phases of cell-mediated immunity to C. neoformans.
authors.affiliation: Veterans Affairs Hospital and Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Olszewski
authors.forename: G B
authors.initials: GB
authors.lastname: Huffnagle
authors.forename: R A
authors.initials: RA
authors.lastname: McDonald
authors.forename: D M
authors.initials: DM
authors.lastname: Lindell
authors.forename: B B
authors.initials: BB
authors.lastname: Moore
authors.forename: D N
authors.initials: DN
authors.lastname: Cook
authors.forename: G B
authors.initials: GB
authors.lastname: Toews
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology; D017353:Gene Deletion; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007111:Immunity, Cellular; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D007106:Immune Sera; D018793:Interleukin-13; D019402:Macrophage Inflammatory Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma