Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation

Chan, Derek V.; Gibson, Heather M.; Aufiero, Barbara; Wilson, Adam J.; Hafner, Mikehl S.; Mi, Qing‐Sheng; Wong, Henry K.

doi:10.1038/gene.2013.57

Cited by 109 publications

(85 citation statements)

References 58 publications

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“…The lack of changes in the overall CD8 subpopulations had been previously observed in frozen samples at later time points [30]. Our data confirms that ipilimumab may be acting preferentially on CD4 T cells, which are known to express higher levels of CTLA-4 [32]. …”

Section: Discussionsupporting

confidence: 89%

Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

et al. 2017

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Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.

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Section: Discussionsupporting

confidence: 89%

Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

et al. 2017

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“…Data from a recent publication demonstrated that NFAT1 increased CTLA-4 promoter activity in CD4 + T cells compared with CD8 + T cells. The expression of CTLA-4 mediated by NFAT1 in CD4 + can potentially be important for anti–CTLA-4 therapy (29). Our laboratory has previously demonstrated that Gal-3 regulates autotaxin through NFAT1 and that high levels of Gal-3 support melanoma growth and metastasis (9).…”

Section: Discussionmentioning

confidence: 99%

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis

et al. 2016

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Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates interleukin-2 expression during T cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL-8 and MMP-3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL-8 and MMP-3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL-8 and MMP-3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP-3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment.

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“…The ergotope peptide-induced Treg cells secreted high levels of IL-10, but not TGF-β, and they were very strong suppressors of CD4 + CD25-effector T cell proliferation. Ergotope peptide treatment increased the surface and intracellular expression of CTLA-4, a costimulatory molecule that negatively regulates T cell activation, in CD4 + CD25 + Treg rather than in CD4 + CD25-T cells (46). CTLA-4 is constitutively expressed by CD4 + CD25 + FOXP3 + Treg and blockade of CTLA-4 interferes with Treg function (47).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Effect of Ergotope Peptides on Collagen-Induced Arthritis by Downregulation of inflammatory and Th1/Th17 Responses and Induction of Regulatory T Cells

Niu

Deng

et al. 2016

Mol Med

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Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th) 1 and 17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it is necessary to find a truly effective and convenient treatment. Several studies have intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find potential ergotope peptides and investigate their effects in treating the animal model of RA and their underlying regulatory mechanisms. First, we selected functional ergotope peptides from 25 overlapping peptides derived from the interleukin 2 receptor (IL-2R) α chain, and then used these peptides to treat collagen-induced arthritis (CIA). We showed ergotope peptides as immunomodulatory factors with great benefits at the clinical and pathologic levels. This effect was associated with inhibition of type II collagen (CII)-specific proliferation and autoantibody production as well as induction of antiergotypic immune response, downregulation of both Th1 and Th17 cells and their related components, and emergence of Treg cells that had suppressive action on autoreactive T cells. We also proved that cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and IL-10 are two important mediators that are critical to Treg suppressive function. Inhibition of Th1 and Th17 in established CIA could be attributed to ergotope-induced Treg cells. Our findings reveal that ergotope peptides induce regulatory immune responses and restore immune tolerance, suggesting that treatment with ergotope peptides may be a novel approach to therapy for RA patients and has good application prospects, with cheap, effective, convenient, wide-spectrum features.

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Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation

Cited by 109 publications

References 58 publications

Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis

Therapeutic Effect of Ergotope Peptides on Collagen-Induced Arthritis by Downregulation of inflammatory and Th1/Th17 Responses and Induction of Regulatory T Cells

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