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* Department of Dermatology,
Department of Cell Biology,
Division of Human Gene Therapy, and
The UAB Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294
Apoptosis plays an important role in eliminating UV-damaged keratinocytes, but its role in UV-induced immune suppression is not clear. Langerhans cells (LCs) may function as inducers of immune suppression. We have shown that LCs derived from mice deficient in the proapoptotic Bid (BH3-interacting death domain protein) gene (Bid KO) resist apoptosis and induce amplified immune responses. In this report, we examined responses in Bid KO mice to UVB exposure. Acute UV exposure led Bid KO mice to develop fewer apoptotic cells and retain a greater fraction of LCs in the epidermal layer of skin in comparison to wild-type mice. Bid KO mice were also markedly resistant to local and systemic UV tolerance induction to hapten sensitization and contact hypersensitivity responses. Elicitation responses and inflammation at skin sensitization sites in UV-treated Bid KO mice were equal to or greater than nonsuppressed control responses. In Bid KO mice, LCs accumulated in lymph nodes to greater numbers, demonstrated longer lifespans, and contained fewer DNA-damaged cells. These studies provide evidence that Bid activation is a critical upstream mediator in UV-induced keratinocyte and LC apoptosis and that its absence abrogates UV-induced immune tolerance.
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1 This work was supported by National Institutes of Health Grants R01-AI50150, R01-CA86172, P30-AR050948, R01-ES015323; U.S. Army Medical Research Acquisition Activity Grant W81XWH-0510296; and a Veterans Affairs Merit Review Award.
2 Address correspondence and reprint requests to Dr. Laura Timares, Department of Dermatology, University of Alabama at Birmingham, 901 19th Street South, BMR2-542, Birmingham, AL 35294-2172. E-mail address: timares{at}uab.edu
3 Abbreviations used in this paper: Bid, BH3-interacting death domain protein; CHS, contact hypersensitivity; CPD, cyclobutane pyrimidine dimer; DAPI, 4',6'-diamidino-2-phenylindole; DC, dendritic cell; DNFB, 2,4-dinitro-1-fluorobenzene; KO, knockout; LC, Langerhans cell; LN, lymph node; RANK, receptor activator of NF-
B; TRANCE, TNF-related activation-induced cytokine; Treg, regulatory T; UVR, ultraviolet radiation; WT, wild type.
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