Regulation of Dendritic Cell Trafficking by the ADP-Ribosyl Cyclase CD38

Abstract

Mice lacking CD38, an ectoenzyme that generates the calcium-mobilizing metabolite cADPR, make reduced T cell-dependent antibody responses. Despite the predicted role for CD38 in B cell activation, we find that CD38 regulates the migration of dendritic cell (DC) precursors from the blood to peripheral sites and controls the migration of mature DCs from sites of inflammation to lymph nodes. Thus, T cells are inefficiently primed in Cd38(-/-) mice, leading to poor humoral immune responses. We also show that CD38 and cADPR modulate calcium mobilization in chemokine-stimulated DCs and are required for the chemotaxis of immature and mature DCs to CCL2, CCL19, CCL21, and CXCL12. Therefore, CD38 regulates adaptive immunity by controlling chemokine receptor signaling in DCs.

CD38 is required for priming by TNF-α: a mechanism for extracellular coordination of cell fate

“…Thus, while CD38 has been shown to play a role in adaptive immunity, with deficient B cell antibody responses and ineffective T cell priming (5,25), its role in innate immunity is less clear.…”

“…Both ADP-ribose and cADPribose can modulate Ca 2ϩ signaling by enhancing the opening potential of TRP channels or ryanodine receptor-gated channels, respectively (9,21). Through this mechanism, CD38 is necessary for the generation of Ca 2ϩ signals downstream of certain G protein-coupled receptors (24,25).…”

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

“…CD38-deficient mice show impaired humoral immune responses, neutrophil chemotaxis, and dendritic cell (DC) trafficking (21)(22)(23). Cells from CD38-deficient mice do not metabolize ecto-NAD ϩ efficiently, and the resulting higher levels of ecto-NAD ϩ lead to a higher level of ART-mediated cell surface protein ADP-ribosylation (24).…”

Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets

“…Thus, our results suggest that CD38 plays a role in novel antiapoptotic signaling pathways but does not directly control glucose signaling in pancreatic ␤-cells. Diabetes 55: 2737-2746, 2006 C D38 is part of an enzyme family with suggested roles in B-cell chronic lymphocytic leukemia, innate and adaptive immunity, smooth muscle contractility, and bone remodeling (1)(2)(3)(4)(5)(6)(7)(8). This multifunctional enzyme is capable of generating cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) from NAD(P)…”