| First Author | Nguyen TTT | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 25 | Pages | e2300987120 |
| PubMed ID | 37307442 | Mgi Jnum | J:353946 |
| Mgi Id | MGI:7493071 | Doi | 10.1073/pnas.2300987120 |
| Citation | Nguyen TTT, et al. (2023) Stimulation of ectopically expressed muscarinic receptors induces IFN-gamma but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells. Proc Natl Acad Sci U S A 120(25):e2300987120 |
| abstractText | T cell antigen receptor stimulation induces tyrosine phosphorylation of downstream signaling molecules and the phosphatidylinositol, Ras, MAPK, and PI3 kinase pathways, leading to T cell activation. Previously, we reported that the G-protein-coupled human muscarinic receptor could bypass tyrosine kinases to activate the phosphatidylinositol pathway and induce interleukin-2 production in Jurkat leukemic T cells. Here, we demonstrate that stimulating G-protein-coupled muscarinic receptors (M1 and synthetic hM3Dq) can activate primary mouse T cells if PLCbeta1 is coexpressed. Resting peripheral hM3Dq+PLCbeta1 (hM3Dq/beta1) T cells did not respond to clozapine, an hM3Dq agonist, unless they were preactivated by TCR and CD28 stimulation which increased hM3Dq and PLCbeta1 expression. This permitted large calcium and phosphorylated ERK responses to clozapine. Clozapine treatment induced high IFN-gamma, CD69, and CD25 expression, but surprisingly did not induce substantial IL-2 in hM3Dq/beta1 T cells. Importantly, costimulation of both muscarinic receptors plus the TCR even led to reduced IL-2 expression, suggesting a selective inhibitory effect of muscarinic receptor costimulation. Stimulation of muscarinic receptors induced strong nuclear translocation of NFAT and NFkappaB and activated AP-1. However, stimulation of hM3Dq led to reduced IL-2 mRNA stability which correlated with an effect on the IL-2 3'UTR activity. Interestingly, stimulation of hM3Dq resulted in reduced pAKT and its downstream pathway. This may explain the inhibitory impact on IL-2 production in hM3Dq/beta1T cells. Moreover, an inhibitor of PI3K reduced IL-2 production in TCR-stimulated hM3Dq/beta1 CD4 T cells, suggesting that activating the pAKT pathway is critical for IL-2 production in T cells. |
