scholarly journals Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits

2021 ◽  
Vol 7 (25) ◽  
pp. eabf8630
Author(s):  
Luciano G. Morosi ◽  
Anabela M. Cutine ◽  
Alejandro J. Cagnoni ◽  
Montana N. Manselle-Cocco ◽  
Diego O. Croci ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
T Cell Immunity ◽  
Trinitrobenzenesulfonic Acid ◽  
Intestinal Homeostasis ◽  
Innate And Adaptive Immunity ◽  
Cell Immunity ◽  
Inflammatory Bowel

Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a β-galactoside–binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent “on-off” circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 β6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1−/− mice exhibited aggravated colitis, St6gal1−/− mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.

scholarly journals IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

2015 ◽  
Vol 36 (4) ◽  
pp. 1259-1273 ◽  
Author(s):  
Virginia Seiffart ◽  
Julia Zoeller ◽  
Robert Klopfleisch ◽  
Munisch Wadwa ◽  
Wiebke Hansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
Cd4 T Cell ◽  
Intestinal Homeostasis ◽  
Crypt Hyperplasia

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

Dendritic Cell-Induced T Cell Non-Responsiveness Is Mediated by FOXP3+ and TGF-beta+IL-10+ CD4+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3891-3891
Author(s):  
Zwi N. Berneman ◽  
Nathalie Cools ◽  
Viggo F.I. Van Tendeloo ◽  
Marc Lenjou ◽  
Griet Nijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Tgf Beta ◽  
Cell Immunity

Abstract Dendritic cells (DC), the professional antigen presenting cells of the immune system, exert important functions both in induction of T cell immunity as well as of tolerance. Previously, it was accepted that the main function of immature DC (iDC) in their in vivo steady state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. However, a growing body of experimental evidence now indicates that traditional DC maturation can no longer be used to distinguish between tolerogenic and immunogenic properties of DC. In this study, we compared the in vitro stimulatory capacity of immature DC (iDC), cytokine cocktail-matured DC (CC-mDC) and poly I:C-matured DC (pIC-mDC) in the absence and presence of antigen. All investigated DC types could induce at least 2 subsets of regulatory T cells. We observed a significant increase in both the number of functionally suppressive transforming growth factor (TGF)-beta+ interleukin (IL)-10+ T cells as well as of CD4+CD25+FOXP3+ T cells within DC/T cell co-cultures as compared to T cell cultures without DC. The induction of these regulatory T cells correlates with in vitro T cell non-responsiveness after co-culture with iDC and CC-mDC, while stimulation with pIC-mDC resulted in reproducible cytomegalovirus pp65 or influenza M1 matrix peptide-specific T cell activation as compared to control cultures in the absence of DC. In addition, the T cell non-responsiveness after stimulation with iDC was shown to be mediated by TGF-beta and IL-10. Moreover, the suppressive capacity of CD4+ T cells activated by iDC and CC-mDC was shown to be transferable when these CD4+ T cells were added to an established T cell response. In contrast, addition of CD4+ T cells stimulated by pIC-mDC made responder T cells refractory to their suppressive activity. In conclusion, we hypothesize that DC have a complementary role in inducing both regulatory T cells and effector T cells, where the final result of antigen-specific T cell activation will depend on the activation state of the DC. This emphasizes the need for proper DC activation when T cell immunity is the desired effect, especially when used in clinical trials.

scholarly journals Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anabelle Visperas ◽  
Jeongsu Do ◽  
Booki Min
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Differentiation ◽  
T Cell Immunity ◽  
Immune Functions ◽  
Effector Cells ◽  
Cell Immunity

The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.

scholarly journals The GPR171 pathway suppresses T cell activation and limits antitumor immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuki Fujiwara ◽  
Robert J. Torphy ◽  
Yi Sun ◽  
Emily N. Miller ◽  
Felix Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
T Cell Immunity ◽  
Antigen Stimulation ◽  
Cell Immunity

AbstractThe recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

scholarly journals SARS-CoV-2 genome-wide mapping of CD8 T cell recognition reveals strong immunodominance and substantial CD8 T cell activation in COVID-19 patients

2020 ◽  
Author(s):  
Sunil Kumar Saini ◽  
Ditte Stampe Hersby ◽  
Tripti Tamhane ◽  
Helle Rus Povlsen ◽  
Susana Patricia Amaya Hernandez ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Disease ◽  
Protein A ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
High Exposure ◽  
Cell Immunity

SummaryTo understand the CD8+ T cell immunity related to viral protection and disease severity in COVID-19, we evaluated the complete SARS-CoV-2 genome (3141 MHC-I binding peptides) to identify immunogenic T cell epitopes, and determine the level of CD8+ T cell involvement using DNA-barcoded peptide-major histocompatibility complex (pMHC) multimers. COVID-19 patients showed strong T cell responses, with up to 25% of all CD8+ lymphocytes specific to SARS-CoV-2-derived immunodominant epitopes, derived from ORF1 (open reading frame 1), ORF3, and Nucleocapsid (N) protein. A strong signature of T cell activation was observed in COVID-19 patients, while no T cell activation was seen in the ‘non-exposed’ and ‘high exposure risk’ healthy donors. Interestingly, patients with severe disease displayed the largest T cell populations with a strong activation profile. These results will have important implications for understanding the T cell immunity to SARS-CoV-2 infection, and how T cell immunity might influence disease development.

scholarly journals The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc–mediated glycolysis

2020 ◽  
Vol 295 (10) ◽  
pp. 3000-3016 ◽  
Author(s):  
Xiumei Wei ◽  
Yu Zhang ◽  
Cheng Li ◽  
Kete Ai ◽  
Kang Li ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Nile Tilapia ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Erk Signaling ◽  
Adaptive Immune ◽  
Cell Immunity ◽  
Evolutionarily Conserved

The mitogen-activated protein kinase (MAPK) cascade is an ancient and evolutionarily conserved signaling pathway involved in numerous physiological processes. Despite great advances in understanding MAPK-mediated regulation of adaptive immune responses in mammals, its contribution to T-cell immunity in early vertebrates remains unclear. Herein, we used Nile tilapia (Oreochromis niloticus) to investigate the regulatory roles of MAPK/extracellular signal–regulated kinase (Erk) signaling in ancestral T-cell immunity of jawed fish. We found that Nile tilapia possesses an evolutionarily conserved MAPK/Erk axis that is activated through a classical three-tier kinase cascade, involving sequential phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (Raf), MAPK/Erk kinase 1/2 (Mek1/2), and Erk1/2. In Nile tilapia, MAPK/Erk signaling participates in adaptive immune responses during bacterial infection. Upon T-cell activation, the MAPK/Erk axis is robustly activated, and MAPK/Erk blockade by specific inhibitors severely impairs T-cell activation. Furthermore, signals from MAPK/Erk were indispensable for primordial T cells to proliferate and exert their effector functions. Mechanistically, activation of the MAPK/Erk axis promoted glycolysis via induction of the transcriptional regulator proto-oncogene c-Myc (c-Myc), to ensure the proper activation and proliferation of fish T cells. Our results reveal the regulatory mechanisms of MAPK/Erk signaling in T-cell immunity in fish and highlight a close link between immune signals and metabolic programs. We propose that regulation of T-cell immunity by MAPK/Erk is a basic and sophisticated strategy that evolved before the emergence of the tetrapod lineage. These findings shed light on the evolution of the adaptive immune system.

scholarly journals Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Swapnil Mahajan ◽  
Vasumathi Kode ◽  
Keshav Bhojak ◽  
Coral Karunakaran ◽  
Kayla Lee ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
T Cell Reactivity ◽  
Shared Epitopes

AbstractThe COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.

scholarly journals Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals

2020 ◽  
Author(s):  
Swapnil Mahajan ◽  
Vasumathi Kode ◽  
Keshav Bhojak ◽  
Coral M. Magdalene ◽  
Kayla Lee ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Common Cold ◽  
Cell Activation ◽  
Severe Disease ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
Cell Immunity

ABSTRACTThe COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the RBD and the non-RBD domain of the spike antigen using a novel TCR-binding algorithm. A selected pool of 11 predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools containing 157 and 158 peptides both in unexposed donors and in convalescent patients suggesting that strong T-cell epitopes are likely to be missed when larger peptide pools are used in assays. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. Whether the presence of pre-existing T-cell immunity provides protection against COVID-19 or contributes to severe disease phenotype remains to be determined in a larger cohort. However, our findings raise the expectation that a significant majority of the global population is likely to have SARS-CoV-2 reactive T-cells because of prior exposure to flu and CMV viruses, in addition to common cold-causing coronaviruses.

scholarly journals Therapeutic Targeting of RUNX-NFATC2 Axis for Acute Promyelocytic Leukemia and T Cell Immunity

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3359-3359
Author(s):  
Hirohito Kubota ◽  
Kana Furuichi ◽  
Tatsuya Masuda ◽  
Toshiya Tatsuta ◽  
Hidefumi Hiramatsu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cell Line ◽  
T Cell Activation ◽  
Cell Activation ◽  
Apoptotic Cell ◽  
Cytokine Expression ◽  
Promyelocytic Leukemia ◽  
T Cell Immunity ◽  
Cell Immunity

Runt-related transcription factor (RUNX) play pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, the role of RUNX remains elusive in acute promyelocytic leukemia (APL). Here, we demonstrate that targeting RUNX1-NFATC2 axis is effective strategy to suppress drug-resistant (DR)-APL cells. Considering the well-established roles of RUNX and NFATC2 in T cell immunity, we also apply targeting RUNX-NFATC2 strategy to suppress T cell activation and xenogeneic graft-versus-host disease (GVHD). Firstly, to investigate whether RUNX1 is essential for APL proliferation and maintenance, we examined cell proliferation of all-trans retinoic acid (ATRA) resistant APL cell line, NB4, using shRNA-mediated knockdown of RUNX1. Profound knockdown of RUNX1 in NB4 cells led to growth suppression and apoptotic cell death. We found that NFATC2 is one of the most consistently up-regulated genes in RUNX1-high expressing APL cells derived from previously reported human clinical samples (GSE2550, GSE13159, GSE61804), and also has RUNX1-binding regions in the promoter from chromatin-immunoprecipitation and sequencing (ChIP-Seq) data (GSE22178, GSE31221). ChIP qPCR assay confirmed the actual binding of RUNX1 in the NFATC2 promotor region of NB4. In addition, luciferase reporter experiments showed NFATC2 promoter significantly increased its reporter activity by RUNX1 over-expression. These results confirmed RUNX1 directly upregulated NFATC2 transcriptional activity. Consistent with these findings, silencing of RUNX1 suppressed the expression of NFATC2. Besides, silencing of NFATC2 in NB4 cells suppressed cell growth and induced apoptotic cell death. Next, the efficacy of our novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole polyamide (Chb-M'), which specifically binds to the consensus RUNX-binding sequence, was examined for NB4. Chb-M' was remarkably more effective against NB4 (IC50 value at nM level) than ATRA and arsenic trioxide. Consistent with association between RUNX1 and NFATC2, Chb-M' suppressed the expression of NFATC2 of NB4. Furthermore, Chb-M′ suppressed NB4 proliferation and NFATC2 expression in xenograft tumor model. Since RUNX and NFATC2 are key regulators of T cell function, we next investigate whether targeting RUNX is also effective for T cell mediated diseases including GVHD. Previous reports showed that RUNX1 directly regulate Th1 cytokine genes such as IL2 and IFNG (Ono M et. al. Nature 2007). From public ChIp-Seq data (ENCODE project. Nature 2012), RUNX1 also binds to NFATC2 promotor region in mouse and human primary CD4 T cells and T-ALL cell line, Jurkat. To study the efficacy of Chb-M' for allo-reactive T-cell activation and proliferation, we performed mixed lymphocyte reaction from different healthy donors using thymidine uptake assay. Compared to control, Chb-M' significantly reduced T cell proliferation. To examine the effect of Chb-M' for T cell cytokine expression, we stimulated peripheral blood mononuclear cells (PBMC) with PMA-ionomycin and measured cytokine expression by quantitative PCR. Results showed that Chb-M'moderately but significantly reduced IL2 , TNF , IFNG and NFATC2 mRNA expression. To investigate whether RUNX is essential for cytokine and NFATC2 expression, we silenced RUNX family by shRNA-knockdown of Jurkat E6.1 cell line. Knockdown of RUNX family reduced IL2 , TNF and NFATC2 expression. These results indicated targeting RUNX-NFATC2 axis is also effective for T cell activation and cytokine expression. Finally, we examined in vivo effect of Chb-M' for xenogeneic GVHD mouse model by transplanting human PBMC onto immunodeficient mice. Compared to control, mice injected by Chb-M' showed almost no sign of GVHD assessed by clinical score and pathological score of lung and liver. Analysing peripheral blood of GVHD mice showed that especially CD4 T cell was decreased and GVHD-associated cytokines including TNF-α and GM-CSF were reduced in Chb-M' injected mice. Taken together, we have shown that RUNX transcriptionally upregulated NFATC2, which is essential for APL proliferation and T cell activation. RUNX-NFATC2 axis can be a novel therapeutic target against DR-APL and GVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals SARS-CoV-2 genome-wide T cell epitope mapping reveals immunodominance and substantial CD8+ T cell activation in COVID-19 patients

2021 ◽  
Vol 6 (58) ◽  
pp. eabf7550
Author(s):  
Sunil Kumar Saini ◽  
Ditte Stampe Hersby ◽  
Tripti Tamhane ◽  
Helle Rus Povlsen ◽  
Susana Patricia Amaya Hernandez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
T Cell Immunity ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Cell Responses ◽  
Cell Immunity

T cells are important for effective viral clearance, elimination of virus-infected cells and long-term disease protection. To examine the full-spectrum of CD8+ T cell immunity in COVID-19, we experimentally evaluated 3141 major histocompatibility (MHC) class I-binding peptides covering the complete SARS-CoV-2 genome. Using DNA-barcoded peptide-MHC complex (pMHC) multimers combined with a T cell phenotype panel, we report a comprehensive list of 122 immunogenic and a subset of immunodominant SARS-CoV-2 T cell epitopes. Substantial CD8+ T cell recognition was observed in COVID-19 patients, with up to 27% of all CD8+ lymphocytes interacting with SARS-CoV-2-derived epitopes. Most immunogenic regions were derived from open reading frame (ORF) 1 and ORF3, with ORF1 containing most of the immunodominant epitopes. CD8+ T cell recognition of lower affinity was also observed in healthy donors toward SARS-CoV-2-derived epitopes. This pre-existing T cell recognition signature was partially overlapping with the epitope landscape observed in COVID-19 patients and may drive the further expansion of T cell responses to SARS-CoV-2 infection. Importantly the phenotype of the SARS-CoV-2-specific CD8+ T cells, revealed a strong T cell activation in COVID-19 patients, while minimal T cell activation was seen in healthy individuals. We found that patients with severe disease displayed significantly larger SARS-CoV-2-specific T cell populations compared to patients with mild diseases and these T cells displayed a robust activation profile. These results further our understanding of T cell immunity to SARS-CoV-2 infection and hypothesize that strong antigen-specific T cell responses are associated with different disease outcomes.

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