Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing agent and its inhibition proved to inhibit T-cell activation. However, the impact of the NAADP signaling on CD4+ T-cell differentiation and plasticity and on the inflammation in tissues other than the central nervous system remains unclear. In this study, we used an antagonist of NAADP signaling, trans-Ned 19, to study the role of NAADP in CD4+ T-cell differentiation and effector function. Partial blockade of NAADP signaling in naïve CD4+ T cells in vitro promoted the differentiation of Th17 cells. Interestingly, trans-Ned 19 also promoted the production of IL-10, co-expression of LAG-3 and CD49b and increased the suppressive capacity of Th17 cells. Moreover, using an IL-17A fate mapping mouse model, we showed that NAADP inhibition promotes conversion of Th17 cells into regulatory T cells in vitro and in vivo. In line with the results, we found that inhibiting NAADP ameliorates disease in a mouse model of intestinal inflammation. Thus, these results reveal a novel function of NAADP in controlling the differentiation and plasticity of CD4+ T cells.
Highlights
When a T cell is presented with cognate antigen by an antigen presenting cell, several Ca2+ mobilizing second messengers are produced: D-myo-inositol 1,4,5-triphosphate (IP3 ), cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP)
These results suggest that NAADP is involved in the early Ca2+ signaling
We found that partial blockade NAADP signaling favored the differentiation of Th1 and Th17
Summary
When a T cell is presented with cognate antigen by an antigen presenting cell, several Ca2+ mobilizing second messengers are produced: D-myo-inositol 1,4,5-triphosphate (IP3 ), cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). They cause the release of Ca2+ from intracellular stores which increases the free cytoplasmic Ca2+ concentration ([Ca2+ ]i ) and induces the activation of store-operated Ca2+ entry (SOCE) [1,2]. Influx of Ca2+ across the plasma membrane leads to a further [Ca2+ ]i increase, which has been shown to play a critical role in T cell activation in multiple models of autoimmunity in vivo [3,4,5]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have