Molecular and Cellular Characterization of Human CD8 T Suppressor Cells

Xu, Zheng; Ho, Sally; Chang, Ching‐Fong; Zhang, Qingyin; Vasilescu, Elena-Rodica; Vlad, George; Suciu‐Foca, Nicole

doi:10.3389/fimmu.2016.00549

Cited by 21 publications

(21 citation statements)

References 105 publications

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“…We recently described a novel human regulatory CD8 + HLA-DR + T cell population present in adult and umbilical venous blood samples ( 5 ) representing a small subset in peripheral blood (PB) or cord blood mononuclear cells (CBMCs). The comparison between CD8 + HLA-DR − and CD8 + HLA-DR + T cells shows similar expression of the co-stimulatory molecule CD28, which differentiates them from the previously characterized CD8 + CD28 −/low T suppressor cells originally generated in vitro by multiple rounds of T cell stimulation by allogenic APCs ( 6 ). Another natural CD8 + Treg population distinguished by expression of CD122 ( 7 ) was described in mice, but has not yet been identified in humans, and appear to exert their suppressor effect via IL-10.…”

Section: Introductionmentioning

confidence: 55%

Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis

et al. 2018

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We have previously identified a human CD8+HLA-DR+ regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8+HLA-DR+ Treg cells which showed great similarities with classical CD4+ cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. CD8+HLA-DR+ Treg-induced suppression on CD8+ responder T cells was abrogated by an anti-PD1 neutralizing antibody. Anti-PD-1 did not abrogate the suppressor effect induced on responder CD4+ T cells. In addition, CD8+HLA-DR+ Treg induced a preferential death on responder CD8+ T cells. This effect was not reversed by PD-1 neutralization. After activation, most CD8+HLA-DR+ Treg acquire programmed death-ligand 1 (PD-L1) expression. Interestingly, PD-L1 may induce apoptosis through CD80 expressed on activated CD8+ responder T cells. After PBMCs stimulation, CD8+HLA-DR+ Treg cells showed an increased frequency of IFN-γ and TNFα positive cells and higher degranulation. These data strongly argue against CD8+HLA-DR+ Treg being exhausted cells. Overall, the data presented in this study indicate that CD8+HLA-DR+ Treg and CD4+FOXP3+ Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.

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Section: Introductionmentioning

confidence: 55%

Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis

et al. 2018

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“…CD8 + T cells were MACS-purified and then cocultivated with APAcCNF-DC for 6 days, followed by their flow cytometry analysis according to the markers proposed for suppressor CD8 + T cells. 45 It was found that, even in the absence of CD4 + T cells, APAcCNF-DC induced significantly higher percentage of IL-10 + cells within the CD8 + CD25 + population (Figure 6A and B), whereas CD8 + CD25 -T cells did not express significant levels of IL-10 (data not shown). The increased IL-10 expression was detected in both IFN-γ + and IFN-γ -CD8 + CD25 + T cells, but a higher percentage of CD8 + CD25 + IFN-γ + T cells expressed IL-10.…”

Section: Differentiated With Ncnf But Not Ccnf and Apaccnf Inducmentioning

confidence: 84%

Functionalization-dependent effects of cellulose nanofibrils on tolerogenic mechanisms of human dendritic cells

Tomić

Ilić

Kokol

et al. 2018

IJN

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BackgroundCellulose nanofibrils (CNF) are attractive nanomaterials for various biomedical applications due to their excellent biocompatibility and biomimetic properties. However, their immunoregulatory properties are insufficiently investigated, especially in relation to their functionalization, which could cause problems during their clinical application.MethodsUsing a model of human dendritic cells (DC), which have a central role in the regulation of immune response, we investigated how differentially functionalized CNF, ie, native (n) CNF, 2,2,6,6-tetramethylpiperidine 1-oxyl radical-oxidized (c) CNF, and 3-aminopropylphosphoric acid-functionalized (APAc) CNF, affect DC properties, their viability, morphology, differentiation and maturation potential, and the capacity to regulate T cell-mediated immune response.ResultsNontoxic doses of APAcCNF displayed the strongest inhibitory effects on DC differentiation, maturation, and T helper (Th) 1 and Th17 polarization capacity, followed by cCNF and nCNF, respectively. These results correlated with a specific pattern of regulatory cytokines production by APAcCNF-DC and their increased capacity to induce suppressive CD8+CD25+IL-10+ regulatory T cells in immunoglobulin-like transcript (ILT)-3- and ILT-4- dependent manner. In contrast, nCNF-DC induced predominantly suppressive CD4+CD25hiFoxP3hi regulatory T cells in indolamine 2,3-dioxygenase-1-dependent manner. Different tolerogenic properties of CNF correlated with their size and APA functionalization, as well as with different expression of CD209 and actin bundles at the place of contact with CNF.ConclusionThe capacity to induce different types of DC-mediated tolerogenic immune responses by functionalized CNF opens new perspectives for their application as well-tolerated nanomaterials in tissue engineering and novel platforms for the therapy of inflammatory T cell-mediated pathologies.

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“…This assumption was underpinned by Battaglia and co-authors [ 10 ] and Heeren and co-authors [ 11 ], who showed that CD8 + FoxP3 + Т cells were more frequent in metastatic tumor-draining lymph nodes in early-stage cervical cancer. Apart from oncological diseases, CD8 Tregs are thought to play an important role in establishment of chronic viral infection, including herpesviruses (EBV, CMV), HCV and HIV (discussed in [ 38 ]). It is also possible that HPV engages CD8 Tregs for maintaining its long-term persistence, which may underlie an increase in the frequency of CD8 Tregs observed at earliest stages of CC progression.…”

Section: Discussionmentioning

confidence: 99%

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

Kurmyshkina

Ковчур

Schegoleva

et al. 2017

Infect Agents Cancer

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BackgroundProcesses and mechanisms responsible for systemic immune suppression in early-stage cervical cancer remain substantially underinvestigated. In this work, we focused on studying the frequencies of circulating regulatory T (CD4 and CD8 Tregs) and NK (NKregs) cells in parallel with assessment of apoptotic markers expression in T cells from patients with preinvasive and microinvasive cervical cancer, with the aim to determine whether up-regulation of apoptosis-associated markers in Т lymphocytes accompanies cervical cancer development and correlates with the change in percentages of regulatory cell populations at systemic level during the initial stages of invasive cervical cancer progression.MethodsFourty two women with histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3, including carcinoma in situ) or cervical cancer (stage IA) and 30 healthy women (control) were enrolled in the study. Peripheral blood samples were taken immediately before surgery or any treatment and immediately subjected to multicolor flow cytometry.ResultsAnalysis of a combination of CD4/CD8, CD25, CD127, and FoxP3 markers revealed a statistically significant increase in the frequencies of Tregs within both the CD4 and CD8 subsets of circulating lymphocytes in patients with CIN3 and stage IA cancer. In contrast, lower numbers of NKregs (defined as CD16dim/negCD56bright subpopulation) and increased CD56dim/CD56bright NK ratio were found in patients compared to controls, with the percentage of CD16brightCD56dim cells (major subtype of circulating NKs) showing no difference. Patients also exhibited an increased expression of CD95 in total peripheral blood T lymphocytes, along with increased level of Annexin V binding to CD95-positive cells, suggesting higher susceptibility of T cells to apoptosis and potential involvement of CD95-dependent pathway in early-stage cervical cancer. Differential analysis of CD4 and CD8 T cells revealed different trends in the change of CD95 expression, confirming that this change likely has different functional significance for these two subsets. A search for correlations between the phenotypic parameters analyzed in this study was performed to demonstrate that women with early neoplastic lesions of the cervix, such as carcinoma in situ and microinvasive carcinoma, displayed a coordinated increase in expression of Treg markers in circulating lymphocytes, along with more pronounced cross-relationships between Treg numbers, CD95 expression on T cells, and apoptosis, compared to the control group.ConclusionsThe results of this study suggest that a diversity of immune regulatory mechanisms that provide support for initial stages of invasive growth in cervical cancer patients includes systemic changes in the ratios between the principal regulatory and effector lymphocyte populations both within adaptive and innate immunity.

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Molecular and Cellular Characterization of Human CD8 T Suppressor Cells

Cited by 21 publications

References 105 publications

Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis

Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis

Functionalization-dependent effects of cellulose nanofibrils on tolerogenic mechanisms of human dendritic cells

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

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