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.
Highlights
T cells have evolved to mount protective response against invading pathogens and cancers, while maintaining tolerance to self-antigens [1,2]. This is governed by the intricate balance between the activation signals and inhibitory signals [3]
T cells require three distinctive receptor mediated activation signals, “signal 1” which is delivered through T cell receptor (TCR) upon recognition of cognate antigen presented by MHC [4,5], “signal 2” through co-stimulatory molecules like CD28, GITR, OX-40, etc. [3], and “signal 3” through cytokine-cytokine receptor interaction [6]
CD38 with several post-translational and epigenetic modifiers for occupancy of NAD+ has been shown to be one of the key dictating factors driving discrete T cell fates. Even this intricate balance appears to be decisive in regulating the suppressive potential of Treg. It can be speculated from the existing studies that Sirt1 mediated deacetylation of FoxP3, a post-translational event that diminishes the suppressive potential of Treg could be instrumental in regulating the differential suppressive activity between CD38hi and CD38lo Treg
Summary
T cells have evolved to mount protective response against invading pathogens and cancers, while maintaining tolerance to self-antigens [1,2]. A similar observation was reported in the cases of esophageal and colorectal cancer (CRC) patients, where expression of CD38 potentiates the suppressive function of MDSCs and is associated with poor survival of patients [35,43] These studies demonstrate that apart from acting as an adhesion molecule through interaction with CD31 on endothelial cells, CD38 could tinker with the cellular events leading to distinctive functional outcome by immune cells. CD38 has been characterized as a marker of terminally exhausted T cells, which are refractory to the PD1 blockade mediated functional rejuvenation [51,52] In agreement with this observation, a study from our group reported that expression of CD38 caused metabolic aberration and compromised anti-tumor response by T cells [13]. These intriguing evidences suggest a complex role of CD38 in regulating T cell response through intervening multiple cellular and molecular pathways
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