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Therapeutic glucocorticoid-induced TNF receptor-mediated amplification of CD4+ T cell responses enhances antiparasitic immunity.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 Mar 01; Vol. 184 (5), pp. 2583-92. Date of Electronic Publication: 2010 Feb 05. - Publication Year :
- 2010
-
Abstract
- Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4(+) T cells, TNF, and IFN-gamma, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4(+) T cell expansion without modulating Treg cell function or protecting conventional CD4(+) T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4(+) T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.
- Subjects :
- Animals
Antibodies, Monoclonal administration & dosage
Antibodies, Monoclonal immunology
Antimony Sodium Gluconate administration & dosage
Antiprotozoal Agents administration & dosage
Apoptosis immunology
CD4-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes cytology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Drug Synergism
Female
Glucocorticoid-Induced TNFR-Related Protein
Immunity, Cellular immunology
Interferon-gamma metabolism
Leishmania donovani drug effects
Leishmania donovani growth & development
Leishmania donovani immunology
Leishmaniasis, Visceral drug therapy
Leishmaniasis, Visceral parasitology
Liver immunology
Liver metabolism
Liver parasitology
Liver Diseases, Parasitic immunology
Liver Diseases, Parasitic metabolism
Liver Diseases, Parasitic parasitology
Male
Mice
Mice, Inbred C57BL
Receptors, Nerve Growth Factor metabolism
Receptors, Tumor Necrosis Factor metabolism
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Tumor Necrosis Factor-alpha metabolism
CD4-Positive T-Lymphocytes immunology
Leishmaniasis, Visceral immunology
Receptors, Nerve Growth Factor immunology
Receptors, Tumor Necrosis Factor immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 184
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 20139272
- Full Text :
- https://doi.org/10.4049/jimmunol.0903080