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CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses¹

Sanjay Pradhan^*, Joseph Genebriera^*, Warren L. Denning, Kumar Felix^*, Craig A. Elmets^*, and Laura Timares^2,*,,,

^* Department of Dermatology, Department of Cell Biology, Department of Pathology, and University of Alabama at Birmingham Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294

The fate of dendritic cells (DCs) after Ag presentation may be DC subset-specific and controlled by many factors. The role of activation-induced apoptosis in regulating DC function is not clear. We investigated the fate of cutaneous DCs (cDCs), specifically Langerhans cells (LCs), and observed that they undergo apoptosis after successful Ag presentation to CD4 T cells. Caspase-specific inhibitors revealed that LC lines use a type II apoptosis pathway in response to CD4 T cells. In support of this, BH3-interacting domain (Bid) protein was present at high levels and specifically cleaved in the presence of Ag-specific T cells. Significant resistance to apoptosis by OT-2 CD4 cells was also observed for Bid knockout (KO) LCs in vitro. To test whether Bid was required to regulate LC function in vivo, we measured contact sensitization and topical immunization responses in Bid KO mice and observed markedly enhanced ear swelling and proliferation responses compared with wild-type mice. Furthermore, when Ag-pulsed Bid KO migratory cDCs were inoculated into wild-type recipients, an increase in both the rate and percentage of expanded OT-2 T cells expressing IFN- was observed. Thus, enhanced Ag presentation function was intrinsic to Bid KO cDCs. Therefore, Bid is an important regulator of LC viability and Ag presentation function.

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 has been supported by grants from the American Cancer Society, Dermatology Foundation, Charlotte Geyer Foundation, and National Institutes of Health Grants R01-AI50150, R01-CA86172, and P30-AR050948, and Department of Defense Grant W81XWH-0510296.

² Address correspondence and reprint requests to Dr. Laura Timares, Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, VH 509 Birmingham, AL 35294. E-mail address: timares{at}uab.edu

³ Abbreviations used in this paper: LC, Langerhans cell; 7-AAD, 7-aminoactinomycin D; AR-LC, apoptosis-resistant LC; BH3, Bcl-2 homology domain 3; Bid, BH3-interacting death domain; cDC, cutaneous DC; DC, dendritic cell; dDC, dermal DC; DNFB, 2–4-dinitrofluorobenzene; HEL, hen egg lysozyme; KO, knockout; TRANCE, TNF-related activation-induced cytokine; WT, wild type.

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