CD38: T Cell Immuno-Metabolic Modulator

Abstract

Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD⁺) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD⁺ glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD⁺ levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD^+, and thus limits its availability to different NAD⁺ consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD⁺ axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD⁺ axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38^-NAD⁺ axis in altering T cell response in various pathophysiological conditions.

Keywords: CD38; NAD+, T cell differentiation; chromatin remodeling; metabolism.

Figure 1

Schematic representation of nicotinamide adenine dinucleotide (NAD⁺) utilizing pathways inside the T cell and their overall effect on T cell response. CD38 is the major mammalian NAD⁺ glycohydrolase (NADase) which metabolizes NAD⁺ and generates cyclic ADP-ribose (cADPR), which promotes T cell activation and proliferations through facilitating Ca²⁺ signaling. CD38 expression also depletes NAD⁺ level and hence affect the enzymatic activity of different NAD⁺ consuming enzymes like Sirt1, PARP1, and ART2.2, which play pivotal role in T cell fate determination.

Figure 2

CD38 mediated regulation of metabolic pathways and chromatin modifications in T cells. CD38 affects the differentiation and effector response of T cells through modulating the metabolic pathways and epigenetic landscape of T cells. On one hand, CD38 curtails the availability of NAD⁺ to Sirt1 and hence attenuates its enzymatic activity which regulates different metabolic and epigenetic pathways in T cells. On the other hand, CD38 inversely regulates glutaminolysis pathways, which not only regulate effector cytokine production in T cells but also produce α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), important epigenetic modifiers.