Mechanosensing through YAP controls T cell activation and metabolism

Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

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Tissue mechanics controls T-cell activation and metabolism

10.1101/581322 ◽

2019 ◽

Author(s):

Kevin P. Meng ◽

Fatemeh S. Majedi ◽

Timothy J. Thauland ◽

Manish J. Butte

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Viral Infections ◽

Autoimmune Diabetes ◽

Tissue Mechanics ◽

Metabolic Reprogramming ◽

Dependent Manner ◽

New Paradigm

SUMMARYUpon immunogenic challenge, lymph nodes become mechanically stiff as immune cells proliferate within their encapsulated environments, and with resolution, they reestablish a soft, baseline state. We found that these mechanical changes in the microenvironment promote and then restrict T-cell activation and metabolic reprogramming. Sensing of tissue mechanics by T cells requires the mechanosensor YAP. Unlike in other cells where YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT into the nucleus. YAP regulates T-cell responses against viral infections and in autoimmune diabetes. Our work reveals a new paradigm whereby tissue mechanics fine-tunes adaptive immune responses in health and disease.One Sentence SummaryTissue mechanics regulates T cells.

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Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity

International Archives of Allergy and Immunology ◽

10.1159/000518448 ◽

2021 ◽

pp. 1-13

Author(s):

Atsushi Tsuge ◽

Sho Yonekura ◽

Satomi Watanabe ◽

Yuta Kurosaki ◽

Shinsuke Hisaka ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Effector T Cells ◽

Contact Hypersensitivity ◽

Dependent Manner ◽

Effector T Cell

Background: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. Methods: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. Results: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3−, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. Conclusion: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

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Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

European Respiratory Journal ◽

10.1183/13993003.00833-2017 ◽

2017 ◽

Vol 50 (4) ◽

pp. 1700833 ◽

Cited By ~ 34

Author(s):

Carolina Cubillos-Zapata ◽

Jose Avendaño-Ortiz ◽

Enrique Hernandez-Jimenez ◽

Victor Toledano ◽

Jose Casas-Martin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Intermittent Hypoxia ◽

Cell Activation ◽

Cell Function ◽

Sleep Apnoea ◽

Orphan Receptor ◽

Dependent Manner ◽

Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

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Human T cell activation. IV. T cell activation and proliferation via the early activation antigen EA 1.

Journal of Experimental Medicine ◽

10.1084/jem.169.3.677 ◽

1989 ◽

Vol 169 (3) ◽

pp. 677-689 ◽

Cited By ~ 43

Author(s):

S Nakamura ◽

S S Sung ◽

J M Bjorndahl ◽

S M Fu

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mrna Levels ◽

Dependent Manner ◽

Early Activation ◽

Human T Cell ◽

Accessory Cells ◽

Activation Antigen

A new mAb G38 was generated against purified EA 1, an early activation antigen. In immunoprecipitation, it was reactive with the same complex precipitated by the initial anti-EA 1 mAb P8. mAb G38 augmented PMA-induced proliferation of PBMC. It was shown to be mitogenic for purified T cells in collaboration with PMA in a dose-dependent manner. This effect was independent of monocytes and other accessory cells. mAb G38 augmented PMA-induced IL-2-R expression. In conjunction with PMA, it induced IL-2 synthesis and secretion. Its effects on IL-2-R and IL-2 expression were documented at both protein and mRNA levels. Both anti-EA 1 mAbs did not induce Ca2+ influx by themselves in PMA-treated T cells. However, the addition of second anti-mouse Ig antibodies induced readily detectable increases in [Ca2+]i. Ca2+-mediated pathways may be utilized as the transduction signal mechanisms. mAb Leu-23 was shown to be reactive with EA 1. mAb Leu-23 was also mitogenic for T cells in the presence of PMA. These findings provide evidence for a functional role for EA 1 in T cell activation and proliferation.

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T cell-T cell activation in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/135245859700300404 ◽

1997 ◽

Vol 3 (4) ◽

pp. 238-242 ◽

Cited By ~ 7

Author(s):

JW Lindsey ◽

RH Kerman ◽

JS Wolinsky

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Viral Infections ◽

Activated T Cells ◽

In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

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Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712107115 ◽

2018 ◽

Vol 115 (10) ◽

pp. 2455-2460 ◽

Cited By ~ 42

Author(s):

Lyndsay Avery ◽

Jessica Filderman ◽

Andrea L. Szymczak-Workman ◽

Lawrence P. Kane

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Chronic Infection ◽

Cell Activation ◽

Effector T Cells ◽

Mtor Signaling ◽

T Cell Exhaustion ◽

Inhibitory Protein ◽

Cell Exhaustion

Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3–deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, and may also contribute to exhaustion by restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is actually more similar to costimulatory receptors that are up-regulated after T cell activation than to a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti–Tim-3 antibodies as therapeutic agents.

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NSOM/QD-Based Visualization of GM1 Serving as Platforms for TCR/CD3 Mediated T-Cell Activation

BioMed Research International ◽

10.1155/2013/276498 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Liyun Zhong ◽

Zhun Zhang ◽

Xiaoxu Lu ◽

Shengde Liu ◽

Crystal Y. Chen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Imaging System ◽

Near Field ◽

Cell Receptor ◽

Dependent Manner ◽

Receptor Complexes ◽

Before And After

Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3) and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM)/immune-labeling quantum dots- (QD-)based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKCθsignaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKCθsignaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKCαβsignaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKCθsignaling cascades and T-cell activation

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Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes

Journal of Experimental Medicine ◽

10.1084/jem.189.2.331 ◽

1999 ◽

Vol 189 (2) ◽

pp. 331-339 ◽

Cited By ~ 311

Author(s):

Petter Höglund ◽

Justine Mintern ◽

Caroline Waltzinger ◽

William Heath ◽

Christophe Benoist ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Beta Cell ◽

T Cell Activation ◽

Cell Activation ◽

Molecular Mimicry ◽

Autoimmune Diabetes ◽

Activated T Cells ◽

Pancreatic Lymph Nodes

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.

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Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Blood ◽

10.1182/blood.v97.12.3851 ◽

2001 ◽

Vol 97 (12) ◽

pp. 3851-3859 ◽

Cited By ~ 44

Author(s):

Sandeep Krishnan ◽

Vishal G. Warke ◽

Madhusoodana P. Nambiar ◽

Henry K. Wong ◽

George C. Tsokos ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Tyrosine Phosphorylation ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Effector T Cells ◽

T Cell Differentiation ◽

Effector T Cell

Human effector T cells have been difficult to isolate and characterize due to their phenotypic and functional similarity to the memory subset. In this study, a biochemical approach was used to analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon γ (IFN-γ) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of CD3ζ and CD3ε signaling subunits coincident with a reduction in surface T-cell receptor (TCR) expression. Because loss of CD3ζ has also been detected in T cells isolated ex vivo from individuals with cancer, chronic viral infection, and autoimmune diseases, the requirements and kinetics of CD3ζ down-regulation were examined. The loss of CD3ζ expression persisted throughout the course of effector T-cell differentiation, was reversible on removal from the activating stimulus, and was modulated by activation conditions. These biochemical changes occurred in effector T cells generated from naive or memory CD4 T-cell precursors and distinguished effector from memory T cells. The results suggest that human effector T-cell differentiation is accompanied by alterations in the TCR signal transduction and that loss of CD3ζ expression may be a feature of chronic T-cell activation and effector generation in vivo.

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Hypoxia is a dominant remodeler of the CD8+ T cell surface proteome relative to activation and regulatory T cell-mediated suppression

10.1101/2021.06.07.447379 ◽

2021 ◽

Author(s):

James Robert Byrnes ◽

Amy M Weeks ◽

Julia Carnevale ◽

Eric Shifrut ◽

Lisa Kirkemo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Surface ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Metabolic Reprogramming ◽

T Cell Function ◽

Human T Cells ◽

Surface Proteome

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the anti-tumor immune response. T cell surface receptors that influence interactions and function in the TME are already proven targets for cancer immunotherapy. However, surface proteome remodeling of primary human T cells in response to suppressive forces in the TME has never been characterized systematically. Using a reductionist cell culture approach with primary human T cells and SILAC-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+ surface proteome (surfaceome). Surprisingly, the CD8+/Treg co-culture only modestly affected the CD8+ surfaceome, but did reverse several activation-induced surfaceomic changes. In contrast, hypoxia dramatically altered the CD8+ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+ T cell surfaceome similarly responded to hypoxia, revealing a novel hypoxia-induced surface receptor program. Our findings are consistent with the premise that hypoxic environments create a metabolic challenge for T cell activation, which may underlie the difficulty encountered in treating solid tumors with immunotherapies. Together, the data presented here provide insight into how suppressive TME factors remodel the T cell surfaceome and represent a valuable resource to inform future therapeutic efforts to enhance T cell function in the TME.

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