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

Abstract

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-γ 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.

Proapoptotic BH3-Only Protein Bid Is Essential For Death Receptor–Induced Apoptosis of Pancreatic β-Cells

“…In other cell types, such as thymocytes or mature T-cells, ligation of death receptors leads to efficient cell killing solely through activation of caspase-8 and the downstream effector caspases (Ϫ3, Ϫ6, and Ϫ7) without the need for Bid-and mitochondrial pathway-mediated amplification of the caspase cascade. Therefore, islets are one of only a handful of primary cell types in which Fas-induced apoptosis is dependent on Bid (16,17,38). No pathology in the pancreas was seen when mice were injected with agonistic anti-Fas antibodies.…”

Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation

“…Furthermore, both direct and indirect effects of DCs on the establishment of an effective immune response are highly dependent on the viability of DCs (4,5). Numerous studies have implicated DC apoptosis in the persistence of infection and the promotion of carcinogenesis (5)(6)(7).…”

A Critical Role for the Proapoptotic Protein Bid in Ultraviolet-Induced Immune Suppression and Cutaneous Apoptosis

“…Control mice had their ears tape-stripped 10× on both dorsal and ventral sides to activate LC migration. After 4 hours, mice were sacrificed and ears recovered and split into dorsal (UV exposed) and ventral (non exposed) sides to float in culture as described previously (30). After 3 days of culture, cells were counted in trypan blue to determine cell recoveries and viability, then adjusted to 4×105 cells/ml PBS.…”

“…In our previous studies, we showed that Bid KO mice could promote enhanced contact hypersensitivity to hapten, and isolated LCs were resistant to apoptosis and able to induce enhanced immunity when transferred to naive recipients (30). Because LC function figures prominently in the mechanism of UV-induced immune suppression, we investigated whether Bid KO mice demonstrated altered responses to UV-induced damage by keratinocytes and LCs.…”