OX40 ligation on activated T cells enhances the control of Cryptococcus neoformans and reduces pulmonary eosinophilia.
Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4(+) Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1-2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-gamma production by CD4(+) T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-gamma. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.
Humphreys
Ian R
IR
Center for Molecular Microbiology and Infection, Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Edwards
Lorna
L
Walzl
Gerhard
G
Rae
Aaron J
AJ
Dougan
Gordon
G
Hill
Sue
S
Hussell
Tracy
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000378:metabolism; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053278:OX40 Ligand; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism*; D048069:Tumor Necrosis Factors
D000276:Adjuvants, Immunologic; D000943:Antigens, Differentiation; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C406562:OX40Ig; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma