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: M A Olszewski, G B Huffnagle, R A McDonald, D M Lindell, B B Moore, D N Cook, G B Toews
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 11 Pg. 6429-36 (Dec 01 2000) ISSN: 0022-1767 [Print] United States
• PMID: 11086082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokine CCL3
• Chemokine CCL4
• Chemokines, CC
• Immune Sera
• Interleukin-13
• Macrophage Inflammatory Proteins
• Interleukin-12
• Interleukin-4
• Immunoglobulin E
• Interferon-gamma

Topics

• Animals
• Cell Movement (immunology)
• Chemokine CCL3
• Chemokine CCL4
• Chemokines, CC (biosynthesis, genetics, immunology, physiology)
• Cryptococcosis (genetics, immunology, microbiology, pathology)
• Cryptococcus neoformans (growth & development, immunology)
• Gene Deletion
• Immune Sera (administration & dosage, pharmacology)
• Immunity, Cellular
• Immunoglobulin E (blood)
• Injections, Intraperitoneal
• Interferon-gamma (biosynthesis)
• Interleukin-12 (biosynthesis)
• Interleukin-13 (biosynthesis)
• Interleukin-4 (biosynthesis)
• Leukocytes (immunology)
• Lung (immunology, microbiology, pathology)
• Lung Diseases, Fungal (genetics, immunology, microbiology, pathology)
• Macrophage Inflammatory Proteins (biosynthesis, genetics, immunology, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Pulmonary Eosinophilia (genetics, immunology)
• Survival Analysis
• T-Lymphocytes (immunology, metabolism)