Genome-Wide Transcriptional Analyses of Islet-Specific CD4+ T Cells Identify Idd9 Genes Controlling Diabetogenic T Cell Function

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

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OX40 regulates pressure overload-induced cardiac hypertrophy and remodelling via CD4+ T-cells

Clinical Science ◽

10.1042/cs20160074 ◽

2016 ◽

Vol 130 (22) ◽

pp. 2061-2071 ◽

Cited By ~ 22

Author(s):

Qing-Qing Wu ◽

Yuan Yuan ◽

Xiao-Han Jiang ◽

Yang Xiao ◽

Zheng Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cardiac Hypertrophy ◽

Cd4 T Cells ◽

Cell Function ◽

Pressure Overload ◽

Cd4 T Cell ◽

Cardiac Remodelling ◽

T Cell Function

Global loss of OX40 aids in resisting pressure overload-induced cardiac remodelling. OX40 KO mice with reconstituted CD4+ T-lymphocytes presented deteriorated cardiac remodelling. OX40 alters the pathology of cardiac remodelling via the modulation of CD4+ T-cell function.

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Modulation of T-Cell Function in the Microenvironment of Emu-TCL1 CLL Bearing Mice By Btki Appears Independent of ITK

Blood ◽

10.1182/blood-2018-99-116444 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3139-3139 ◽

Cited By ~ 1

Author(s):

Mark-Alexander Schwarzbich ◽

Arantxa Romero-Toledo ◽

Melanie Frigault ◽

John G. Gribben

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Research Funding ◽

Synapse Formation ◽

Cell Function ◽

Cytotoxic T Cells ◽

Tumour Microenvironment ◽

T Cell Function ◽

Cell Synapse

Abstract Background: Chronic lymphocytic leukemia (CLL) development is associated with global immunodeficiency including T-cell exhaustion. We hypothesise that repairing T cell functions would improve outcome and decrease infectious complications which cause significant morbidity in CLL patients. Chronic B-cell receptor (BCR) activation as well as close interactions with the tumour microenvironment promote survival of malignant CLL B-cells, supporting their ability to induce immune suppression. To date, the most clinically successful approach to BCR-signalling inhibition is by the use of BTK inhibitors (BTKi). It has been suggested that the BTKi Ibrutinib has the ability to modulate T-helper cell polarity from Th2 to Th1 and thus would be a step towards repairing CLL associated T-cell defects (1). We were therefore interested to determine whether the second generation BTKi Acalabrutinib which has no reported inhibitory capacity towards ITK would have similar effects than Ibrutinib in modulating T cell responses. Materials and Methods: To address this question in vivo C57/Bl6 animals 2.5 months of age were injected with 40x10e6 purified CLL B-cells pooled from Eµ-TCL1 mice with CLL. When peripheral blood CLL load reached >10% animals were randomized (mean day 14) to either vehicle treatment (2% HPBD) or Acalabrutinib treatment (0.15 mg/l in 2% HPBC) for 21 days. 17 animals were group were analysed. Splenic cells were isolated, the cellular component characterized by CyTOF and T cell function assessed by multi-parameter flow cytometry and T-cell synapse formation assay. Results: Treatment with Acalabrutinib resulted in increased expression of IL2 (p<0.0001) in CD4+ T cells and decreased expression of IL4 among both CD4+ T cells (p=0.0016) but not CD8+ T-cells. There was a reduction in Interferon gamma production in both CD4 T-cells (p=0.0463) and CD8+ T-cells (p=0.0064) with Acalabrutinib treatment. In addition, treatment resulted in an increase in CD107a+/CD107a- ratio among both CD44+ and CD44- CD8+ cytotoxic T-cells. This effect was pronounced in the antigen experienced CD44+ cytotoxic T-cells (p<0.0001) but only moderate (p=0.0056) in the CD44- cytotoxic T-cells. Lastly, we find a statistically significant increase in T-cell synapse area (p<0.0001) with Acalabrutinib treatment (Figure 1). Conclusion: We find that treatment with both Ibrutinib and Acalabrutinib result in a similar shift of T cell function with cytokine secretion with increased IL2 and decreased IL4. T-cells in CLL have increased Interferon gamma production (2) and the observed decrease seen with Acalabrutinib is in keeping with a normalization of T cell function. Moreover, overall CD8+ T-cell function is increased with Acalabrutinib treatment as evidenced by an increase in cytotoxic T-cell function and immune synapse formation. We speculate that inhibition of ITK is not the leading cause for this phenomenon as Acalabrutinib does not have inhibitory capacity toward this kinase. These changes suggest that BTKi modulate T cell mediated immune responses indirectly via either their effects in the CLL B-cell or myeloid cells in the tumour microenvironment. References Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539-49. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612-21. Disclosures Frigault: Acerta Pharma: Employment. Gribben:Abbvie: Honoraria; Acerta Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Unum: Equity Ownership; Roche: Honoraria; TG Therapeutics: Honoraria; NIH: Research Funding; Medical Research Council: Research Funding; Cancer Research UK: Research Funding; Kite: Honoraria; Pharmacyclics: Honoraria; Novartis: Honoraria.

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ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging

Molecular Imaging and Biology ◽

10.1007/s11307-016-1032-z ◽

2016 ◽

Vol 19 (4) ◽

pp. 599-609 ◽

Cited By ~ 22

Author(s):

Amanda C. Freise ◽

Kirstin A. Zettlitz ◽

Felix B. Salazar ◽

Xiang Lu ◽

Richard Tavaré ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

T Cell Function

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High Levels Of IL-27 Occur In Newly Diagnosed Acute Myeloid Leukemia (AML) and May Influence Outcome By Suppressing T Cell Function

Blood ◽

10.1182/blood.v122.21.2567.2567 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2567-2567

Author(s):

Nicole Stephens ◽

Sawa Ito ◽

Stephen A. Strickland ◽

Bipin N. Savani ◽

Madan Jagasia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Induction Chemotherapy ◽

Cd4 T Cells ◽

Lymphocyte Count ◽

Cell Function ◽

Conflicts Of Interest ◽

Remission Induction ◽

Dependent Manner ◽

T Cell Function

Abstract Between presentation and remission of AML, loss of leukemia burden and the recovery of normal hematopoiesis are likely to be associated with major changes in cytokine profiles which could inform pathophysiology of hematopoiesis and immune recovery and may be predictive for outcome. However cytokine fluctuations in AML before and after induction chemotherapy are not well characterized. To profile the cytokine signatures of patients with AML, we analyzed 57 cytokines, chemokines, and growth factors in blood of 11 patients with AML (mean age 58 years; 31-69) undergoing conventional remission induction chemotherapy enrolled into an investigational study (VICCHEM 1073). Plasma was obtained from heparinized peripheral blood collected at onset of leukemia, 8-14 days, and 22-35 days after the initiation of induction chemotherapy and also from 12 healthy donors. Cytokine levels were measured in duplicate using magnetic beads based Luminex assay (Affymetrix, CA, USA). Compared with normal controls, 5 cytokine patterns were observed. i) levels significantly lower at onset of leukemia, and lowest 8-14 days after induction correlating with lymphocyte count: GM-CSF, M-CSF, PDGF-AA, EGF, FGF basic, IL1b, IL-2,IL4, IL10, IL12p40, IL12p70, IL13, IL15, IL17a, IL22, IL23p19, TNF beta, TNF alpha, IFN alpha, IFN gamma, TGF alpha, MCP3, LIF, Granzyme B, sFAS ligand, TRAIL, (p<0.05). Most of these cytokines are predominantly produced by T cells or other immune cells. ii) levels significantly higher in AML through chemotherapy induction and recovery: IL-27 (p=0.002), MPO, IL2Ra, IL-21, , IP-10, MIG, MIP1 alpha, SDF-1, MCP1(p<0.05), HGF (p=0.05), VEGF (p=0.07), IL1Ra (p=0.058). These cytokines are predominantly produced by stromal cells. iii) levels significantly higher at the onset of leukemia and correlating with lymphocyte count: CD40 ligand (p<0.05). iv) levels significantly lower at onset of leukemia but inversely correlated with lymphocyte count; Flt3-ligand, sFAS (p<0.05). v) No significant differences and fluctuation: NGF, GRO alpha, IL1a, IL3, IL5, IL6, IL7, IL8, IL9, MIP1b, SCF. Among the cytokines persistently elevated in AML, IL-27 was significantly higher in patients who did not achieve complete remission after induction chemotherapy (p=0.03). To investigate the biological consequences of elevated IL-27 in the AML microenvironment, we examined the effect of IL-27 on T-cell function. Previous studies in mice show that IL-27 rapidly induces PD-L1 expression on naïve CD4+ T-cells. Human CD4+ naïve and CD4+ cells were isolated from healthy volunteers (n=4) according to RoboSep protocols (Stemcell Technologies, Vancouver, Canada), then incubated with IL-27 or IL-6 for up to 72 hours. IL-27 was found to induce PD-L1 expression in a time and dose-dependent manner especially in CD4+ naïve and central memory populations. These findings support other findings that AML suppresses protective antileukemic immune responses and cause T cell exhaustion. IL-27 production induced by AML cells may explain exhaustion of CD4+ T-cells through increased PD-L1 expression. Targeting IL-27 may improve immune function in AML and lead to better survival. Disclosures: No relevant conflicts of interest to declare.

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Suppression of Activation and Costimulatory Signaling in Splenic CD4+ T Cells after Trauma-Hemorrhage Reduces T-Cell Function

American Journal Of Pathology ◽

10.2353/ajpath.2009.081174 ◽

2009 ◽

Vol 175 (4) ◽

pp. 1504-1514 ◽

Cited By ~ 14

Author(s):

Chi-Hsun Hsieh ◽

Jun-Te Hsu ◽

Ya-Ching Hsieh ◽

Michael Frink ◽

Raghavan Raju ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

T Cell Function

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Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection

Journal of Virology ◽

10.1128/jvi.00963-10 ◽

2010 ◽

Vol 84 (20) ◽

pp. 10501-10509 ◽

Cited By ~ 17

Author(s):

Jie Liu ◽

Tracy J. Ruckwardt ◽

Man Chen ◽

John D. Nicewonger ◽

Teresa R. Johnson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

T Cell Response ◽

Viral Clearance ◽

Cd4 T Cell ◽

T Cell Function ◽

Specific Subset

ABSTRACT The role of epitope-specific regulatory CD4 T cells in modulating CD8 T-cell-mediated immunopathology during acute viral infection has not been well defined. In the murine model of respiratory syncytial virus (RSV) infection, CD8 T cells play an important role in both viral clearance and immunopathology. We have previously characterized two RSV epitope-specific CD4 T-cell responses with distinct phenotypic properties. One of them, the IAbM209-specific subset, constitutively expresses FoxP3 and modulates CD8 T-cell function in vitro. We show here that the IAbM209-specific CD4 T-cell response regulates CD8 T-cell function in vivo and is associated with diminished RSV-induced illness without affecting viral clearance at the site of infection. Achieving the optimal balance of regulatory and effector T-cell function is an important consideration for designing future vaccines.

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IFN-γ from CD4 T Cells Is Essential for Host Survival and Enhances CD8 T Cell Function during Mycobacterium tuberculosis Infection

The Journal of Immunology ◽

10.4049/jimmunol.1200061 ◽

2012 ◽

Vol 190 (1) ◽

pp. 270-277 ◽

Cited By ~ 143

Author(s):

Angela M. Green ◽

Robert DiFazio ◽

JoAnne L. Flynn

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection ◽

T Cell Function ◽

Ifn Γ

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Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics.

Journal of Experimental Medicine ◽

10.1084/jem.181.4.1365 ◽

1995 ◽

Vol 181 (4) ◽

pp. 1365-1372 ◽

Cited By ~ 467

Author(s):

M R Klein ◽

C A van Baalen ◽

A M Holwerda ◽

S R Kerkhof Garde ◽

R J Bende ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

Cd4 Counts ◽

Rapid Progressors ◽

T Cell Function ◽

Hiv 1 ◽

Ctl Responses

To gain more insight into the role of HIV-1-specific cytotoxic T lymphocytes (CTL) in the pathogenesis of AIDS, we investigated temporal relations between HIV-1 Gag-specific precursor CTL (CTLp), HIV-1 viral load, CD4+ T cell counts, and T cell function. Six HIV-1-infected subjects, who were asymptomatic for more than 8 yr with CD4+ counts > 500 cells/mm3, were compared with six subjects who progressed to AIDS within 5 yr after HIV-1 seroconversion. In the long-term asymptomatics, persistent HIV-1 Gag-specific CTL responses and very low numbers of HIV-1-infected CD4+ T cells coincided with normal and stable CD4+ counts and preserved CD3 mAb-induced T cell reactivity for more than 8 yr. In five out of six rapid progressors Gag-specific CTLp were also detected. However, early in infection the number of circulating HIV-1-infected CD4+ T cells increased despite strong and mounting Gag-specific CTL responses. During subsequent clinical progression to AIDS, loss of Gag-specific CTLp coincided with precipitating CD4+ counts and severe deterioration of T cell function. The possible relationships of HIV-1 Gag-specific CTLp to disease progression are discussed.

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