scholarly journals Macrophages Control the Bioavailability of Vitamin D and Vitamin D-Regulated T Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Villalba Lopez ◽  
Fatima A. H. Al-Jaberi ◽  
Anders Woetmann ◽  
Niels Ødum ◽  
Charlotte Menné Bonefeld ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Effector Function ◽  
M1 Macrophages ◽  
Cell Responses ◽  
Cell Effector Function ◽  
Cell Effector

The active form of vitamin D3 (1,25(OH)2D3) has a great impact on T cell effector function. Thus, 1,25(OH)2D3 promotes T helper 2 (Th2) and regulatory T (Treg) cell function and concomitantly inhibits Th1 and Th17 cell function. Thus, it is believed that vitamin D exerts anti-inflammatory effects. However, vitamin D binding protein (DBP) strongly binds both 1,25(OH)2D3 and the precursor 25(OH)D3, leaving only a minor fraction of vitamin D in the free, bioavailable form. Accordingly, DBP in physiological concentrations would be expected to block the effect of vitamin D on T cells and dendritic cells. In the present study, we show that pro-inflammatory, monocyte-derived M1 macrophages express very high levels of the 25(OH)D-1α-hydroxylase CYP27B1 that enables them to convert 25(OH)D3 into 1,25(OH)2D3 even in the presence of physiological concentrations of DBP. Co-cultivation of M1 macrophages with T cells allows them to overcome the sequestering of 25(OH)D3 by DBP and to produce sufficient levels of 1,25(OH)2D3 to affect T cell effector function. This study suggests that in highly inflammatory conditions, M1 macrophages can produce sufficient levels of 1,25(OH)2D3 to modify T cell responses and thereby reduce T cell-mediated inflammation via a vitamin D-mediated negative feed-back loop.

Obesity results in higher PD-1-mediated T-cell suppression but greater T-cell effector functions following blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 65-65 ◽  
Author(s):  
Robert J. Canter ◽  
Ethan Aguilar ◽  
Ziming Wang ◽  
Catherine Le ◽  
Lam Khuat ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Murine Cytomegalovirus ◽  
Obese Mice ◽  
Effector Functions ◽  
Cell Responses ◽  
The Central Nervous System ◽  
The Impact ◽  
Cell Effector

65 Background: Obesity is increasingly prevalent and viewed as a critical co-factor in many pathologic conditions due to metabolic, inflammatory and immune perturbations. We performed a multi-species evaluation of the impact of obesity T cell effector functions and markers of immune exhaustion. Methods: We examined the impact of obesity on PD-1 and T cell-mediated responses across different pre-clinical models (tumor, infection, and autoimmune encephalomyelitis [EAE]) and species (mouse, dog, non-human primate, and human). Results: CD4 and CD8 T cells from obese mice, dogs, non-human primates and humans displayed increases in memory T cells and PD-1 expression, as well as impaired proliferative responses compared to lean controls, indicating a greater degree of T cell exhaustion at baseline. Following immunization with myelin oligodendrocyte glycoprotein, obese mice were resistant to induction of EAE, correlating with reduced antigen-specific CD4 T cells in the central nervous system. Administration of anti-PD-1 resulted in restoration of EAE and increased antigen-specific T cell numbers in obese mice. Tumors in obese mice exhibited accelerated growth compared to lean mice, and T cells displayed higher PD-1 expression correlating with RNAseq/molecular signatures of exhaustion compared to tumor-bearing lean mice. PD-1 blockade resulted in marked anti-tumor effects only in obese mice, and not lean. Impaired viral resistance to murine cytomegalovirus (MCMV) resulted was seen in obese mice, associated with increased PD-1/PD-L1 expression, which was reversible by PD-1/PD-L1 blockade. Conclusions: Obesity results in an increase in PD-1/PD-L1 expression and inhibition of T cell responses across species, and blockade not only reverses this inhibition but also leads to markedly augmented T cell effector responses compared to lean counterparts where no effects were observed. These results highlight how the immune system has evolved to control T cell responses using checkpoints contingent on dynamic host conditions and have translational relevance for predicting both efficacy and toxicity in clinical immuno-oncology.

HPV16 E629-38-specific T cells kill cervical carcinoma cells despite partial evasion of T-cell effector function

2008 ◽  
Vol 122 (12) ◽  
pp. 2791-2799 ◽  
Author(s):  
Karen J. Thomas ◽  
Kelly L. Smith ◽  
Sarah J. Youde ◽  
Mererid Evans ◽  
Alison N. Fiander ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cervical Carcinoma ◽  
Effector Function ◽  
Carcinoma Cells ◽  
Cell Effector Function ◽  
Cell Effector

scholarly journals Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Christina P. Martins ◽  
Lee A. New ◽  
Erin C. O’Connor ◽  
Dana M. Previte ◽  
Kasey R. Cargill ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Metabolic Reprogramming ◽  
Cell Responses ◽  
T Cell Function

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

scholarly journals Thymic stromal lymphopoietin limits primary and recall CD8+ T-cell anti-viral responses

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Risa Ebina-Shibuya ◽  
Erin E West ◽  
Rosanne Spolski ◽  
Peng Li ◽  
Jangsuk Oh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Function ◽  
Influenza Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Thymic Stromal Lymphopoietin ◽  
Direct Role ◽  
Cell Responses

Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells generated after influenza infection. However, TSLP inhibited memory CD8+ T-cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8+ T-cell responses in response to viral infection, findings with potential translational implications.

scholarly journals Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells

2020 ◽  
Vol 8 (2) ◽  
pp. e000691 ◽  
Author(s):  
Kelly-Anne Masterman ◽  
Oscar L Haigh ◽  
Kirsteen M Tullett ◽  
Ingrid M Leal-Rojas ◽  
Carina Walpole ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Effector Function ◽  
Immunogenic Tumor ◽  
Cross Presentation ◽  
Cell Responses

BackgroundDendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs.MethodsHuman anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells.ResultsCLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.ConclusionsThese data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.

Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 801-806 ◽  
Author(s):  
Kent W. Christopherson ◽  
Antoinette F. Hood ◽  
Jeffrey B. Travers ◽  
Heather Ramsey ◽  
Robert A. Hromas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Skin Diseases ◽  
Effector Function ◽  
T Cell Migration ◽  
T Cell Infiltration ◽  
Secondary Lymphoid Organs ◽  
Cell Effector Function ◽  
Cell Effector

Abstract The signals that mediate T-cell infiltration during T-cell autoimmune diseases are poorly understood. The chemokine CCL21 (originally isolated by us and others as Exodus-2/6Ckine/SLC/TCA4) is highly potent and highly specific for stimulating T-cell migration. However, it is thought to be expressed only in secondary lymphoid organs, directing naive T cells to areas of antigen presentation. It is not thought to play a role in T-cell effector function during a normal immune response. In this study we tested the expression of T-cell chemokines and their receptors during T-cell autoimmune infiltrative skin diseases. By using immunohistology it was found that the expression of CCL21 but not CCL19 or 20 was highly induced in endothelial cells of T-cell autoimmune diseases. The receptor for CCL21, CCR7, was also found to be highly expressed on the infiltrating T cells, most of which expressed the memory CD45Ro phenotype. These data imply that the usual loss of CCL21 responsiveness in the normal development of memory T-cell effector function does not hold for autoimmune skin diseases.

scholarly journals Yap suppresses T cell function and infiltration in the tumor microenvironment

2019 ◽  
Author(s):  
Eleni Stampouloglou ◽  
Anthony Federico ◽  
Emily Slaby ◽  
Stefano Monti ◽  
Gregory L. Szeto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cell Responses

ABSTRACTA major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

scholarly journals Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

2016 ◽  
Vol 213 (8) ◽  
pp. 1589-1608 ◽  
Author(s):  
Cindy S. Ma ◽  
Natalie Wong ◽  
Geetha Rao ◽  
Akira Nguyen ◽  
Danielle T. Avery ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Cd4 T Cells ◽  
Clinical Manifestations ◽  
Effector Function ◽  
Cd4 T Cell ◽  
The Impact ◽  
Cell Effector Function ◽  
Cell Effector

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.

Augmentation of Post-Transplant Immunity: Antigen Encounter at Time of Hematopoietic Stem Cell Transplantation Enhances Antigen-Specific Donor T Cell Responses in the Post-Transplant Repertoire.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2246-2246
Author(s):  
Craig A. Mullen ◽  
Ulker Kocak ◽  
Joanne L. Shaw ◽  
Shahram Mori
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Spleen Cells ◽  
Hematopoietic Stem ◽  
Cd8 Cells ◽  
Post Transplant ◽  
Cell Responses ◽  
Donor T Cells

Abstract After transplant the immune system is reconstituted by cells derived from both hematopoietic stem cells and peripheral expansion of differentiated donor T cells. Immune function is poor despite transplantation of mature lymphocytes from immune competent donors. We tested the hypothesis that early antigen encounter at the time of cell transplant would enhance desired donor T cell responses in the post-transplant repertoire. 2 independent models of peptide-specific T cell responses were studied. Model 1 : The model for CD4 cells employed T cells from transgenic DO11.11 mice that constitutively express the T cell receptor for the class II restricted ovalbumin (OVA) peptide 323–339. Fig 1: Early exposure to OVA antigen enhances clonal expansion of OVA specific transgenic T-cells following syngeneic BMT. Lethally irradiated BALB/c mice were injected with 300 μg of OVA peptide in CFA or CFA alone subcutaneously one day before transplantation (D-1). The transplanted mice received 2x106 transgenic OVA specific T-cells and 6x106 non-transgenic naive BALB/c bone marrow cells. At 2 days (A) and 7weeks (B) following BMT, draining lymph nodes were isolated and examined for the presence of OVA-specific T-cells using FITC-labeled KJ-126 antibody and PE-labeled anti mouse CD4 antibody. Naïve BALB/c animals were used as negative controls (C). The absolute number of antigen-specific T-cells was determined by multiplying the total cells recovered with the percentage of OVA-specific CD4+ T-cells identified by flow. Figure Figure Model 2: The model for CD8 cells employed nontransgenic H2-Db-restricted T cell responses to the influenza nucleoprotein peptide 366–374. Fig 2: Antigen specific CD8+ cells in antigen-exposed animals are functionally active. Donor SW mice were immunized three times by ip injection of virus-infected spleen cells. Recipient C57BL/6 animals underwent BMT using influenza-immune donors spleen cells and bone marrow (10x106 and 4x106 respectively). Some transplant recipients were exposed to influenza virus on D-1. Ten days following BMT, the animals were sacrificed and spleens were isolated and stimulated in vitro with 2 μg of NP peptide. After two rounds of stimulation, the splenocytes were assayed by intracellular cytokine assay for the secretion of IFNg by staining with PE-anti IFNγ and FITC-anti-CD8 antibodies. The results are representative of three experiments (total number n=4/experimental group). Figure Figure Encounter with specific antigen at the time of T cell transplantation led to clonal expansion of donor T cells and preservation of donor T cell function in the post-transplant immune environment. Antigen-specific donor T cell function was poor if antigen encounter was delayed or omitted. Severe parent>F1 graft versus host reactions blocked the effect of early antigen exposure.

scholarly journals Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3673-3681 ◽  
Author(s):  
Philip O. Scumpia ◽  
Matthew J. Delano ◽  
Kindra M. Kelly-Scumpia ◽  
Jason S. Weinstein ◽  
James L. Wynn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immune Dysfunction ◽  
Effector Function ◽  
Cd4 T Cell ◽  
Agonistic Antibody ◽  
Adaptive Immune ◽  
Cell Effector Function ◽  
Cell Effector

Abstract Apoptosis of CD4+ T cells and TH2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell–dependent IgM and IgG2a antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4+ T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3ζ. Five days following immunization, CD4+ T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-γ but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4+ T-cell proliferation, increased TH1 and TH2 cytokine production, partially prevented CD3ζ down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4+ T cells but not CD25+ regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4+ T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.

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