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OX40 Ligation on Activated T Cells Enhances the Control of Cryptococcus neoformans and Reduces Pulmonary Eosinophilia

Ian R. Humphreys^*, Lorna Edwards^*, Gerhard Walzl^*, Aaron J. Rae^*, Gordon Dougan^*, Sue Hill and Tracy Hussell^1,*

^* Center for Molecular Microbiology and Infection, Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, United Kingdom; and Xenova Research, Cambridge, United Kingdom

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- 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-. 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.

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The JI 2003 170: 5807-5808. [Full Text]  

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