scholarly journals CD5 dynamically calibrates basal NF-κB signaling in T cells during thymic development and peripheral activation

2020 ◽  
Vol 117 (25) ◽  
pp. 14342-14353
Author(s):  
Courtney A. Matson ◽  
Seeyoung Choi ◽  
Ferenc Livak ◽  
Bin Zhao ◽  
Apratim Mitra ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Surface Glycoprotein ◽  
Effector Memory ◽  
Peripheral T Cells ◽  
Peripheral Activation ◽  
Self Peptides

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hiT cells expressed more of the NF-κB p65 protein than CD5locells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hiT cells over CD5loones. Taken together, these data suggest a two-step model whereby the strength of self-peptide–induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.

Parasite species regulates T cell activation in human malaria

2021 ◽  
Author(s):  
Florian Bach ◽  
Diana Munoz Sandoval ◽  
Michalina Mazurczyk ◽  
Yrene Themistocleous ◽  
Thomas A Rawlinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasmodium Vivax ◽  
T Cell Activation ◽  
Cell Activation ◽  
Parasite Species ◽  
Field Isolate ◽  
Effector Memory ◽  
Lymphoid Tissues ◽  
Systems Immunology

Plasmodium vivax offers unique challenges for malaria control and may prove a more difficult species to eradicate than Plasmodium falciparum. Yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. In this study, we inoculated human volunteers with a clonal field isolate of P. vivax and used systems immunology tools to track their response through infection and convalescence. Our data reveal Plasmodium vivax triggers an acute phase response that shares remarkable overlap with that of P. falciparum, suggesting a hardwired innate response that does not differentiate between parasite species. This leads to the global recruitment of innate-like and adaptive T cells into lymphoid tissues where up to one quarter of the T cell compartment is activated. Heterogeneous effector memory-like CD4+ T cells dominate this response and their activation coincides with collateral tissue damage. Remarkably, comparative transcriptional analyses show that P. falciparum drives even higher levels of T cell activation; diverging T cell responses may therefore explain why falciparum malaria more frequently causes severe disease.

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

scholarly journals Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

2020 ◽  
Author(s):  
Anno Saris ◽  
Tom D.Y. Reijnders ◽  
Esther J. Nossent ◽  
Alex R. Schuurman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Effector Memory ◽  
Activated T Cells ◽  
Immune Profile ◽  
Prolonged Icu Stay

AbstractOur understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood.SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

EP.WE.805From bench to bedside; A rationale for Immunotherapy in the adjuvant setting for Oesophageal cancer

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Noel Donlon ◽  
Maria Davern ◽  
Andrew Sheppard ◽  
John Reynolds ◽  
Joanne Lysaght
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Single Agent ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Post Surgery ◽  
Post Operative Period

Abstract Background Immunotherapy is being intensively investigated for its utilisation in the curative setting as a single agent and in the multimodal setting, however, the most appropriate time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumour immunity perioperatively to provide a rationale for adjuvant immunotherapy. Methods Systemic immunity was immunophenotyped pre and post-oesophagectomy on days 0, 1, 3, 7 and week 6 by flow cytometry (n = 14). The frequency of circulating lymphocytes, T cells, cytotoxic and helper T lymphocytes was profiled longitudinally including the proportion of T cell subsets in circulation. This study also profiled immune checkpoint expression on circulating T cells including: PD-1, CTLA-4, TIGIT, TIM-3, LAG-3, PD-L1 and PD-L2. Markers of immunogenicity (calreticulin, HMGB1 and MIC-A/B) were also assessed. Results The frequency of circulating CD27 + T cells increases sequentially in the immediate post-operative period peaking on day 7 in OAC patients. (p < 0.01) There is a sequential decrease in the percentage of effector memory and central memory T cells in circulation and an increase in the percentage of naïve T cells in peripheral circulation of OAC patients in the immediate post-operative period. The expression of CTLA-4 on the surface of circulating CD4 + T cells decreases 6 weeks post-operatively in OAC patients. Conclusions We observed increased T cell activation and immune checkpoints immediately post-surgery with returns to baseline by week 6. These results suggest that immune checkpoint inhibitors such as anti-PD-1 may be beneficial immediately post-surgery to maintain T cell activation and prevent exhaustion of this increased population of activated T cells observed immediately post-surgery.

scholarly journals Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

1986 ◽  
Vol 164 (3) ◽  
pp. 709-722 ◽  
Author(s):  
T R Malek ◽  
G Ortega ◽  
C Chan ◽  
R A Kroczek ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Accessory Cells ◽  
Peripheral T Cells ◽  
Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Alexander Starodub ◽  
Sarina Anne Piha-Paul ◽  
Raghad Karim ◽  
Curtis Ruegg ◽  
Victoria Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastroesophageal Junction ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Advanced Solid Tumors

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .

scholarly journals Molecular Mechanisms of Immunomodulation Properties of Mesenchymal Stromal Cells: A New Insight into the Role of ICAM-1

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Yury Rubtsov ◽  
Кirill Goryunov ◽  
Аndrey Romanov ◽  
Yulia Suzdaltseva ◽  
George Sharonov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mesenchymal Stromal Cells ◽  
T Cell Activation ◽  
Stromal Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Mixed Cultures ◽  
Activated T Cells

Mesenchymal stromal cells (MSC) control excessive inflammation and create a microenvironment for tissue repair protecting from chronic inflammation and tissue fibrosis. We examined the molecular mechanisms of MSC immunomodulatory function in mixed cultures of human adipose-derived MSC with lymphocytes. Our data show that MSC promote unstimulated lymphocyte survival potentially by an increase in antigen presentation. Under inflammatory conditions, mimicked by stimulation of TCR in lymphocytes, MSC suppress activation and proliferation of stimulated T cells. Immunosuppression is accompanied by downregulation of IL-2Rαthat negatively affects the survival of activated T cells. MSC upregulate transcription of indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS), which generate products negatively affecting T cell function. Both MSC and lymphocytes dramatically increase the surface ICAM-1 level in mixed cultures. Antibody-mediated blockage of surface ICAM-1 partially releases MSC-mediated immune suppression in vitro. Our data suggest that MSC have cell-intrinsic molecular programs depending on the inflammatory microenvironment. We speculate that MSC sense soluble factors and respond by surface ICAM-1 upregulation. ICAM-1 is involved in the control of T cell activation leading to immunosuppression or modest stimulation depending on the T cell status. Immunomodulation by MSC ranging from support of naive T cell survival to immunosuppression of activated T cells may affect the tissue microenvironment protecting from aberrant regeneration.

Redox regulation of T-cell receptor signaling

2015 ◽  
Vol 396 (5) ◽  
pp. 555-569 ◽  
Author(s):  
Luca Simeoni ◽  
Ivan Bogeski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Receptor ◽  
T Cell Function

Abstract T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

scholarly journals Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jing Pan ◽  
Yao Chen ◽  
Qi Zhang ◽  
Achia Khatun ◽  
Katie Palen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lung Tumor ◽  
Peptide Vaccine ◽  
Effector Memory ◽  
Mouse Lung ◽  
Lung Tumorigenesis

AbstractExpressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8+ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.

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