scholarly journals Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

2020 ◽  
Author(s):  
Cheleka A.M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
Munyaradzi Musvosvi ◽  
One B Dintwe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Cd4 T Cell ◽  
Remote Infection ◽  
Ifn Γ

AbstractBackgroundRecent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection.MethodsHealthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterized M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+.FindingsCFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection.InterpretationRecent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection.

Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-γ

2007 ◽  
Vol 292 (6) ◽  
pp. G1630-G1640 ◽  
Author(s):  
Iris Dotan ◽  
Matthieu Allez ◽  
Atsushi Nakazawa ◽  
Jens Brimnes ◽  
Micoll Schulder-Katz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel ◽  
Ifn Γ

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-γ, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-γ indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

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.

CD4 + T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

2019 ◽  
Vol 49 (6) ◽  
pp. 653-662
Author(s):  
Ryo Nakagawa ◽  
Ryosuke Muroyama ◽  
Chisato Saeki ◽  
Tsunekazu Oikawa ◽  
Yoshimi Kaise ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Differentially Expressed ◽  
Primary Biliary Cholangitis

scholarly journals Modulation of LPS-Induced CD4+ T-Cell Activation and Apoptosis by Antioxidants in Untreated Asymptomatic HIV Infected Participants: AnIn VitroStudy

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
S. Mburu ◽  
J. L. Marnewick ◽  
A. Abayomi ◽  
H. Ipp
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vitamin C ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Annexin V ◽  
Cd4 T Cell ◽  
Hiv Positive ◽  
Cd25 Expression

Persistent immune activation characterises HIV infection and is associated with depletion of CD4+ T-cells and increased risk of disease progression. Early loss of gut mucosal integrity results in the translocation of microbial products such as lipopolysaccharide (LPS) into the systemic circulation. This is an important source of on-going immune stimulation. The purpose of this study was to determine levels of CD4+ T-cell activation (%CD25 expression) and apoptosis (% annexin V/7-AAD) in asymptomatic, untreated HIV infection at baseline and after stimulation with LPS and incubation with or without vitamin C and N-acetylcysteine. LPS induced a significant (P<0.03) increase in %CD25 expression, annexin V, and 7-AAD in HIV positive individuals. NAC in combination with vitamin C, significantly (P=0.0018) reduced activation and early apoptosis of CD4+ T-cells to a greater degree than with either antioxidant alone. Certain combinations of antioxidants could be important in reducing the harmful effects of chronic immune activation and thereby limit CD4+ T-cell depletion. Importantly, we showed that CD4+ T-cells of the HIV positive group responded better to a combination of the antioxidants at this stage than those of the controls. Therefore, appropriate intervention at this asymptomatic stage could rescue the cells before repetitive activation results in the death of CD4+ T-cells.

The Inflammation Signaling Molecule ATP Regulates Human CD4+ T Cell Functions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3901-3901
Author(s):  
Sara Trabanelli ◽  
Darina Očadlíková ◽  
Sara Gulinelli ◽  
Antonio Curti ◽  
Francesco di Virgilio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Extracellular Atp ◽  
Cd4 T Cell ◽  
Cell Functions ◽  
Atp Concentration ◽  
High Concentrations

Abstract Abstract 3901 Adenosine 5'-triphosphate (ATP) is emerging as an extracellular signaling molecule playing a pivotal role in several cellular processes, through specific cell membrane purinergic P2 receptors (P2Rs). Under physiological conditions, ATP is present in the extracellular space at low concentrations (1-10 nM), whereas during inflammation and tumor cell growth ATP is present in the extracellular space at high concentrations, when 5–10 mM of ATP are quickly released from cytoplasm following plasma membrane damage or membrane stretching. For these reasons, extracellular ATP, via activation of P2Rs, might be an important regulator of inflammatory and immune response. CD4+ T cells are often exposed to different ATP concentrations in healthy or in injured/inflamed tissues. In the present study, we investigated the expression of purinergic P2 receptors (P2Rs) on human activated and regulatory CD4+ T cells and tested the lymphocyte functions in presence of low (1-10 nM), intermediate (250 nM) and high (1 mM) concentration of extracellular ATP. We assessed CD4+ T cells proliferation, apoptosis, phenotype, cytokine release, migration and matrix/cells adhesion. We show that activated CD4+ T cells express all P2Rs subtypes, whereas Tregs do not express P2X6 and P2Y2. At a functional level, low concentrations of extracellular ATP do not modulate CD4+ T cell functions. An increase in ATP concentration (250 nM) stimulates CD4+ T cells during activation: activated CD4+ T cells enhance their proliferation, the secretion of several cytokines critical for T cell functions (IL-2, IL-1b, IFN-g, IL-8), the expression of adhesion molecules (CD49d and CD54) and the capacity to adhere to cellular matrix or to other cells. Tregs seem to be unaffected by 250 nM of ATP. In contrast, high concentrations of ATP (1 mM) “turn off” activated CD4+ T cells and “turn on” Tregs. 1 mM of ATP inhibits activation of CD4+ T cells, by enhancing apoptosis and diminishing proliferation, cell-adhesion and the release of pro-inflammatory cytokines. Conversely, 1 mM of ATP attracts Tregs and stimulates their proliferation and their capacity to adhere to other cells. Moreover, Tregs cultured in presence of 1 mM of extracellular ATP are more efficient in inhibiting T cell proliferation. In summary, the present data show that the concentration of extracellular ATP regulates CD4+ T cell functions. Low ATP concentrations, as in physiological conditions, do not affect CD4+ T cell functions, whereas any enhancement of ATP concentration alters CD4+ T cell behavior. Specifically, a small increase stimulates CD4+ T cell activation, whereas a high increase inhibits CD4+ T cell activation and promotes the immunosuppression Tregs-mediated. We propose that the present in vitro data might explain how in vivo ATP regulates the behavior of activated CD4+ T cells and Tregs in case of inflammation or tumor cell growth. A small enhancement of ATP concentration occurs at the beginning of an inflammatory state or at the first stages of tumor growth; these ATP concentrations alert CD4+ T cells to the presence of a possible damage, which does not yet require Tregs involvement. In contrast, in case of severe inflammation, high ATP concentrations might prevent a further involvement of activated CD4+ T cells and promotes Tregs recruitment, avoiding hyper-inflammation. In case of advanced stages of tumorigenesis, high ATP concentration might be a tumor-escape mechanism, by killing activated CD4+ T cells and by attracting Tregs to surround the tumor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shiguang Yu ◽  
Morgan Tripod ◽  
Ulus Atasoy ◽  
Jing Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Th17 Cell Differentiation

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

scholarly journals Differential Expression of Activation Markers by Mycobacterium tuberculosis-specific CD4+ T Cell Distinguishes Extrapulmonary From Pulmonary Tuberculosis and Latent Infection

2019 ◽  
Vol 71 (8) ◽  
pp. 1905-1911 ◽  
Author(s):  
Paulo S Silveira-Mattos ◽  
Beatriz Barreto-Duarte ◽  
Beatriz Vasconcelos ◽  
Kiyoshi F Fukutani ◽  
Caian L Vinhaes ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Activation Markers ◽  
Timely Initiation ◽  
Latent Tb

Abstract Background Diagnosis of active tuberculosis (ATB) currently relies on detection of Mycobacterium tuberculosis (Mtb). Identifying patients with extrapulmonary TB (EPTB) remains challenging because microbiological confirmation is often not possible. Highly accurate blood-based tests could improve diagnosis of both EPTB and pulmonary TB (PTB) and timely initiation of anti-TB therapy. Methods A case-control study was performed using discriminant analyses to validate an approach using Mtb-specific CD4+T-cell activation markers in blood to discriminate PTB and EPTB from latent TB infection (LTBI) as well as EPTB from PTB in 270 Brazilian individuals. We further tested the effect of human immunodeficiency virus (HIV) coinfection on diagnostic performance. Frequencies of interferon-γ +CD4+T cells expressing CD38, HLADR, and/or Ki67 were assessed by flow cytometry. Results EPTB and PTB were associated with higher frequencies of CD4+T cells expressing CD38, HLADR, or Ki67 compared with LTBI (all P values &lt; .001). Moreover, frequencies of HLADR+ (P = .03) or Ki67+ (P &lt; .001) cells accurately distinguished EPTB from PTB. HIV infection did not affect the capacity of these markers to distinguish ATB from LTBI or EPTB from PTB. Conclusions Cell activation markers in Mtb-specific CD4+T cells distinguished ATB from LTBI and EPTB from PTB, regardless of HIV infection status. These parameters provide an attractive approach for developing blood-based diagnostic tests for both active and latent TB.

scholarly journals Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

2019 ◽  
Vol 221 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Catherine Riou ◽  
Nishtha Jhilmeet ◽  
Molebogeng X Rangaka ◽  
Robert J Wilkinson ◽  
Katalin A Wilkinson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Antiretroviral Treatment ◽  
Cell Activation ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Tuberculosis Antigen

Abstract The reconstitution of Mycobacterium tuberculosis antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in a high tuberculosis endemic area is described. Restoration of the antigen-specific CD4 T-cell subsets mirrored the overall CD4 T-cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known M. tuberculosis sensitization determined by interferon-γ release assay, 12/23 participants had no M. tuberculosis-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T-cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.

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