mTOR and other effector kinase signals that impact T cell function and activity

Abstract

T cells play important roles in autoimmune diseases and cancer. Following the cloning of the T cell receptor (TCR), the race was on to map signaling proteins that contributed to T cell activation downstream of the TCR as well as co-stimulatory molecules such as CD28. We term this "canonical TCR signaling" here. More recently, it has been appreciated that T cells need to accommodate increased metabolic needs that stem from T cell activation in order to function properly. A central role herein has emerged for mechanistic/mammalian target of rapamycin (mTOR). In this review we briefly cover canonical TCR signaling to set the stage for discussion on mTOR signaling, mRNA translation, and metabolic adaptation in T cells. We also discuss the role of mTOR in follicular helper T cells, regulatory T cells, and other T cell subsets. Our lab recently uncovered that "tonic signals", which pass through proximal TCR signaling components, are robustly and selectively transduced to mTOR to promote baseline translation of various mRNA targets. We discuss insights on (tonic) mTOR signaling in the context of T cell function in autoimmune diseases such as lupus as well as in cancer immunotherapy through CAR-T cell or checkpoint blockade approaches. K E Y W O R D Sautoimmune, cancer, mammalian target of rapamycin, signaling, T cell, tonic | 135 MYERS Et al

Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond

“…Given the ADNP/EB1 interactions, together with our current results, these findings indicate modulations of immune reactivity by ADNP concentrations. Interestingly, we found further sexual dichotomies, for example, in female mice, Adnp/NAP regulate splenic Adnp expression and further regulate genes that that impact T cell function and activity such as Mtor, and in males, NAP regulates Mtor (Hacohen-Kleiman et al 2018;Myers et al 2019). Additionally, we discovered Adnp/NAP regulation of Kdm5d (a Y chromosome gene) associated with male phenotype development (Hacohen-Kleiman et al 2018).…”

Increased baseline RASGRP1 signals Enhance Stem Cell Fitness during Native Hematopoiesis

“…Hematopoietic stem- and progenitor-cell homeostasis is regulated by the BM niche 29 and cytokines released by stromal cells in this niche 30 . Cytokines can trigger RAS activation and RASGTP transmits signals to downstream effector kinase pathways, such as the RAF-MEK-ERK, Phosphatidylinositol 3-kinase (PI3K)-AKT and mTORC1-S6 and mTORC2-AKT pathways 5,21,31,32 . In T-ALL cell lines, KRAS G12D causes high baseline RASGTP levels 5,33 , whereas overexpressed RASGRP1 constitutively loads RAS with GTP and RASGTP is constantly hydrolyzed back to inactive RASGDP 5 ( Figure 1D ).…”

Immunosuppressive Activity of Artemisia argyi Extract and Isolated Compounds

“…The rising calcium concentration in the cytosol causes dephosphorylation and thereby unmasking of the nuclear location sequence of the nuclear factor of activated T cells (NFAT) via second messenger and phosphatase activation (Srikanth et al, 2017). On a further axis the mitogen-activated protein kinase (MAPK) pathway is triggered, resulting the formation of activator protein 1 (AP-1) and its nuclear transport (Myers et al, 2019). The third axis induces phosphorylation of nuclear factor of the kappa-light-polypeptidegene enhancer in B cells inhibitor (IkB), leading to its degradation.…”

“…Subsequently, the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) is released for nuclear transport (Sun, 2012). The transcription factors NFAT, NF-kB, and AP-1 all bind to the interleukin-2 (il-2) gene to allow transcription and secretion of interleukin-2 (IL-2) (Myers et al, 2019). IL-2 autocrinally stimulates T cell proliferation, and thus, is crucial for a proper immune response.…”