Abstract:High-resolution mass spectrometry maps the cytotoxic T lymphocyte (CTL) proteome and the impact of mammalian target of rapamycin complex 1 (mTORC1) on CTLs. The CTL proteome was dominated by metabolic regulators and granzymes and mTORC1 selectively repressed and promoted expression of subset of CTL proteins (~10%). These included key CTL effector molecules, signaling proteins and a subset of metabolic enzymes. Proteomic data highlighted the potential for mTORC1 negative control of phosphatidylinositol (3,4,5)-… Show more
“…In contrast, CD25 expression, which was already present on the surface of T lymphoblasts, was only increased when T cells were activated on the aCD3+aCD28+ICAM-1-coated stiff 100 kPa gels (Figure 4C and D), whereas its gene expression was increased from 0.5 kPa (Figure 2C). These last results may be explained by the differences between transcriptomic and proteomic analyses that have already been reported (Hukelmann et al, 2016). They might also reflect a difference in sensitivity for the different measurements performed.10.7554/eLife.23190.015Figure 4.Cytokine production is sensitive to a wide range of stiffness.Production of ( A ) IFNγ (n Donors : 13) and ( B ) TNFα (n Donors : 10) on PA-gels of varying stiffness.…”
T cells are mechanosensitive but the effect of stiffness on their functions is still debated. We characterize herein how human primary CD4+ T cell functions are affected by stiffness within the physiological Young’s modulus range of 0.5 kPa to 100 kPa. Stiffness modulates T lymphocyte migration and morphological changes induced by TCR/CD3 triggering. Stiffness also increases TCR-induced immune system, metabolism and cell-cycle-related genes. Yet, upon TCR/CD3 stimulation, while cytokine production increases within a wide range of stiffness, from hundreds of Pa to hundreds of kPa, T cell metabolic properties and cell cycle progression are only increased by the highest stiffness tested (100 kPa). Finally, mechanical properties of adherent antigen-presenting cells modulate cytokine production by T cells. Together, these results reveal that T cells discriminate between the wide range of stiffness values found in the body and adapt their responses accordingly.DOI:
http://dx.doi.org/10.7554/eLife.23190.001
“…In contrast, CD25 expression, which was already present on the surface of T lymphoblasts, was only increased when T cells were activated on the aCD3+aCD28+ICAM-1-coated stiff 100 kPa gels (Figure 4C and D), whereas its gene expression was increased from 0.5 kPa (Figure 2C). These last results may be explained by the differences between transcriptomic and proteomic analyses that have already been reported (Hukelmann et al, 2016). They might also reflect a difference in sensitivity for the different measurements performed.10.7554/eLife.23190.015Figure 4.Cytokine production is sensitive to a wide range of stiffness.Production of ( A ) IFNγ (n Donors : 13) and ( B ) TNFα (n Donors : 10) on PA-gels of varying stiffness.…”
T cells are mechanosensitive but the effect of stiffness on their functions is still debated. We characterize herein how human primary CD4+ T cell functions are affected by stiffness within the physiological Young’s modulus range of 0.5 kPa to 100 kPa. Stiffness modulates T lymphocyte migration and morphological changes induced by TCR/CD3 triggering. Stiffness also increases TCR-induced immune system, metabolism and cell-cycle-related genes. Yet, upon TCR/CD3 stimulation, while cytokine production increases within a wide range of stiffness, from hundreds of Pa to hundreds of kPa, T cell metabolic properties and cell cycle progression are only increased by the highest stiffness tested (100 kPa). Finally, mechanical properties of adherent antigen-presenting cells modulate cytokine production by T cells. Together, these results reveal that T cells discriminate between the wide range of stiffness values found in the body and adapt their responses accordingly.DOI:
http://dx.doi.org/10.7554/eLife.23190.001
“…It is
important to keep in mind that PI3Kδ regulates other pathways in addition
mTOR, and conversely, that mTOR is also regulated byPI3K-independent
pathways8. Moreover, mTOR regulates
the expression of PTEN such that treatment of T cells with
rapamycin can actually increase PI3K signalling in T cells84, potentially exacerbating aspects of hyperactive
PI3Kδ signalling in APDS.…”
Section: Treatment Options For Patients With Apdsmentioning
Primary immunodeficiencies are inherited disorders of the immune system,
often caused by the mutation of genes required for lymphocyte development and
activation. Recently, several studies have identified gain-of-function mutations
in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which
encodes p110δ) and PIK3R1 (which encodes p85α)
that cause a combined immunodeficiency syndrome, referred to as activated
PI3Kδ syndrome (APDS) or p110δ-activating mutation causing
senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically,
both loss-of-function and gain-of-function mutations that affect these genes
lead to immunosuppression, albeit via different mechanisms. Here, we review the
roles of PI3Kδ in adaptive immunity, describe the clinical manifestations
and mechanisms of disease in APDS and highlight new insights into PI3Kδ
gleaned from these patients, as well as implications of these findings for
clinical therapy.
“…Proteomic analysis of Raptor-deficient T cells shows that expression of key transcription factors in metabolic reprogramming (MYC, YY1, GABPA, SREBF1) and components of the translational machinery are dependent upon mTORC1 (Tan et al, 2017), highlighting the central role of mTORC1 in anabolic T cell growth. Moreover, in cytotoxic CD8 + T cells, proteomic analyses have shown that rapamycin treatment to inhibit mTORC1 causes a reduction in cell size and protein content associated with changes in abundance (up as well as down) of approximately 10% of the proteome, including reductions in glucose transporters, and enzymes in the glycolysis and cholesterol synthesis metabolic pathways, as well as of the PtdIns(3,4,5)P3 phosphatase PTEN, and key effector proteins such as IFN-γ, perforin granzyme, and TNFα (Hukelmann et al, 2016). These changes are generally related to rapamycin-induced reductions in transcription of the encoding genes, although outside of these pathways clear mTORC1-dependent differences in protein levels in the absence of effects on transcription are measurable.…”
Section: Metabolic Sensing By Mtor and Competition For Nutrients Withmentioning
Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.
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