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* Department of Immunology and Center for Cancer Immunology Research, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030; and
Dermatology Research Unit, Melanoma and Skin Cancer Research Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
The UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP+ skin was grafted onto mast cell-deficient mice, we found that GFP+ mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4+ and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the University of Sydney R&D Scheme, a National Health and Medical Research Council C. J. Martin Fellowship (307726 to S.N.B.), and grants from the National Cancer Institute (CA112660 and CA75575 to S.E.U.). The animal, histology, and flow cytometry facilities at the M.D. Anderson Cancer Center are supported in part by National Cancer Institute Cancer Center Support Grant CA 16672.
2 Address correspondence and reprint requests to Dr. Stephen E. Ullrich, Department of Immunology-902, M.D. Anderson Cancer Center, 1515 University of Texas, Holcombe Boulevard, Houston, TX 77030. E-mail address: sullrich{at}mdanderson.org
3 Abbreviations used in this paper: BMMC, bone marrow-derived mast cell; CHS, contact hypersensitivity; DLN, draining lymph node; LC, Langerhans cell; PAF, platelet-activating factor; DNFB, 2,4-dinitro-1-fluorobenzene; CT, cycle threshold.
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