Furthermore, the metabolic demands of different helper T cell subsets are not identical. Over the past decade, it has become increasingly clear that metabolic reprogramming of the T cell needs to occur to enable the transition from the naïve to the activated state, and these metabolic changes are necessary to support T cell proliferation and effector functions. Additionally, activated, IL-2 secreting T cells are remarkably proliferative, and as such they have a high metabolic demand. The coordinated activity of three transcription factors, NFAT, NFkB, and AP-1, is required for the production of IL-2 ( Figure 2). Simplified scheme of the canonical pMHC/TCR signaling pathway viewed as a linear relay system from TCR to transcription factors through proximal kinases, adapters, second messengers, and effector kinase pathways.Ĭoncomitant with T cell activation are changes in gene expression and the synthesis of new proteins, one of which is the cytokine IL-2, a critical cytokine that supports T cell survival. Proximal TCR Signaling, Adapters, and Secondary Messengers. 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. Our lab recently uncovered that “tonic signals” known to pass through proximal TCR signaling components are robustly and selectively transduced to mTOR to promote baseline translation of various mRNA targets. We also discuss the role of mTOR for in follicular helper T cells, regulatory T cells, and other T cell subsets. In this review we briefly cover canonical TCR signaling to set the stage for discussion on mTOR signaling in T cells, mRNA translation, and metabolic adaptation. A central role herein has emerged for mammalian target of rapamycin, mTOR. More recent, it has been appreciated that T cells need to accommodate increased metabolic needs that stem from T cell activation in order to function properly. We term this “canonical TCR signaling” here. 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. T cells play important roles in autoimmune diseases and cancers.
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