Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)

Abstract An urgent need exists to devise strategies to augment antiviral immune responses in patients with HIV who are virologically well controlled and immunologically stable on highly active antiretroviral therapy (HAART). The objective of this study was to compare the immunomodulatory effects of the cytokines interleukin (IL)–21 with IL-15 on CD8 T cells in patients with HIV RNA of less than 50 copies/mL and CD4 counts greater than 200 cells/mm.3 Patient CD8 T cells displayed skewed maturation and decreased perforin expression compared with healthy controls. Culture of freshly isolated patient peripheral-blood mononuclear cells (PBMCs) for 5 hours to 5 days with IL-21 resulted in up-regulation of perforin in CD8 T cells, including memory and effector subsets and virus-specific T cells. IL-21 did not induce T-cell activation or proliferation, nor did it augment T-cell receptor (TCR)–induced degranulation. Treatment of patient PBMCs with IL-15 resulted in induction of perforin in association with lymphocyte proliferation and augmentation of TCR-induced degranulation. Patient CD8 T cells were more responsive to cytokine effects than the cells of healthy volunteers. We conclude that CD8 T cells of patients with HIV can be modulated by IL-21 to increase perforin expression without undergoing overt cellular activation. IL-21 could potentially be useful for its perforin-enhancing properties in anti-HIV immunotherapy.

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Deoxynivalenol Affects Proliferation and Expression of Activation-Related Molecules in Major Porcine T-Cell Subsets

Toxins ◽

10.3390/toxins11110644 ◽

2019 ◽

Vol 11 (11) ◽

pp. 644 ◽

Cited By ~ 2

Author(s):

Vatzia ◽

Pierron ◽

Saalmüller ◽

Mayer ◽

Gerner

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Mononuclear Cells ◽

Animal Feed ◽

Γδ T Cells ◽

T Cell Subsets ◽

Peripheral Blood Mononuclear

The Fusarium mycotoxin deoxynivalenol (DON) contaminates animal feed worldwide. In vivo, DON modifies the cellular protein synthesis, thereby also affecting the immune system. However, the functional consequences of this are still ill-defined. In this study, peripheral blood mononuclear cells from healthy pigs were incubated with different DON concentrations in the presence of Concanavalin A (ConA), a plant-derived polyclonal T-cell stimulant. T-cell subsets were investigated for proliferation and expression of CD8α, CD27, and CD28, which are involved in activation and costimulation of porcine T cells. A clear decrease in proliferation of all ConA-stimulated major T-cell subsets (CD4+, CD8+, and γδ T cells) was observed in DON concentrations higher than 0.4 µM. This applied in particular to naïve CD4+ and CD8+ T cells. From 0.8 μM onwards, DON induced a reduction of CD8α (CD4+) and CD27 expression (CD4+ and CD8+ T cells). CD28 expression was diminished in CD4+ and CD8+ T cells at a concentration of 1.6 µM DON. None of these effects were observed with the DON-derivative deepoxy-deoxynivalenol (DOM-1) at 16 µM. These results indicate that DON reduces T-cell proliferation and the expression of molecules involved in T-cell activation, providing a molecular basis for some of the described immunosuppressive effects of DON.

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DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease

Immunotherapy Advances ◽

10.1093/immadv/ltaa004 ◽

2020 ◽

Author(s):

M E Jacobs ◽

J N Pouw ◽

M A Olde Nordkamp ◽

T R D J Radstake ◽

E F A Leijten ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Cytokine Production ◽

Inverse Correlation ◽

T Cell Response ◽

Peripheral Blood Mononuclear ◽

Psoriatic Disease

Abstract Background Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods By flow cytometry we analyzed peripheral blood mononuclear cells of patients with psoriasis (n=20) or psoriatic arthritis (n=21), and healthy individuals (n=7). We measured CD155, TIGIT and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and -negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results High CD155 expression associates with TNF production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

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Characterization of the T-Cell Receptor Vβ Repertoire in the Human Immune Response against Leishmania Parasites

Infection and Immunity ◽

10.1128/iai.00265-06 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4757-4765 ◽

Cited By ~ 16

Author(s):

Jorge Clarêncio ◽

Camila I. de Oliveira ◽

Glória Bomfim ◽

Margarida M. Pompeu ◽

Maria Jania Teixeira ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Cell Receptor ◽

Peripheral Blood Mononuclear ◽

Cell Clones ◽

Human Immune Response ◽

Lymph Node Cells

ABSTRACT In order to explore a possible presence of hyperreactive T-cell clones in human cutaneous leishmaniasis (CL), we have investigated, by flow cytometry, the expression of Vβ chains of T-cell receptors (TCRs) in the following types of cells: (i) peripheral blood mononuclear cells (PBMCs) from CL patients, which were then compared to those from normal volunteers; (ii) unstimulated and soluble Leishmania antigen-stimulated draining lymph node cells from CL patients; (iii) PBMCs from volunteers before versus after Leishmania immunization; and (iv) PBMCs from healthy volunteers that were primed in vitro with live Leishmania parasites. Our results show a modulation in the TCR Vβ repertoire during CL and after antigen stimulation of patients' cells. Vaccination, however, leads to a broad expansion of different Vβ TCRs. We also observed an association between TCR Vβ12 expression, T-cell activation, and gamma interferon production upon in vitro priming with Leishmania. Collectively, these results both indicate that infection with live parasites or exposure to parasite antigen can modulate the TCR Vβ repertoire and suggest that TCR Vβ12 may be implicated in the response to Leishmania.

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T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state

Journal of Experimental Medicine ◽

10.1084/jem.20062610 ◽

2007 ◽

Vol 204 (11) ◽

pp. 2747-2757 ◽

Cited By ~ 30

Author(s):

Pia P. Yachi ◽

Carina Lotz ◽

Jeanette Ampudia ◽

Nicholas R.J. Gascoigne

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cd8 T Cell ◽

Cell Receptor ◽

Endogenous Peptides ◽

Foreign Peptide ◽

Antigen Presenting

T cells are extremely sensitive in their ability to find minute amounts of antigenic peptide in the midst of many endogenous peptides presented on an antigen-presenting cell. The role of endogenous peptides in the recognition of foreign peptide and hence in T cell activation has remained controversial for CD8+ T cell activation. We showed previously that in a CD8+ T cell hybridoma, nonstimulatory endogenous peptides enhance T cell sensitivity to antigen by increasing the coreceptor function of CD8. However, others were not able to detect such enhancement in naive and activated CD8+ T cells. Here, we show that endogenous peptides substantially enhance the ability of T cells to detect antigen, an effect measurable by up-regulation of activation or maturation markers and by increased effector function. This enhancement is most pronounced in thymocytes, moderate in naive T cells, and mild in effector T cells. The importance of endogenous peptides is inversely proportional to the agonist activity of the stimulatory peptide presented. Unlike for CD4+ T cells, the T cell receptor of CD8+ T cells does not distinguish between endogenous peptides for their ability to enhance antigen recognition.

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Decreased Expression of the CD3ζ Chain in T Cells Infiltrating the Synovial Membrane of Patients with Osteoarthritis

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.1.195-202.2004 ◽

2004 ◽

Vol 11 (1) ◽

pp. 195-202 ◽

Cited By ~ 15

Author(s):

Lazaros I. Sakkas ◽

George Koussidis ◽

Efthimios Avgerinos ◽

John Gaughan ◽

Chris D. Platsoucas

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Activated T Cells ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

T Cell Stimulation ◽

Inflammatory Infiltrates

ABSTRACT Osteoarthritis (OA) is a heterogeneous disease which rheumatologists consider to be noninflammatory. However, recent studies suggest that, at least in certain patients, OA is an inflammatory disease and that patients often exhibit inflammatory infiltrates in the synovial membranes (SMs) of macrophages and activated T cells expressing proinflammatory cytokines. We report here that the expression of CD3ζ is significantly decreased in T cells infiltrating the SMs of patients with OA. The CD3ζ chain is involved in the T-cell signal transduction cascade, which is initiated by the engagement of the T-cell antigen receptor and which culminates in T-cell activation. Double immunofluorescence of single-cell suspensions derived from the SMs from nine patients with OA revealed significantly increased proportions of CD3ε-positive (CD3ε+) cells compared with the proportions of CD3ζ-positive (CD3ζ+) T cells (means ± standard errors of the means, 80.48% ± 3.92% and 69.02% ± 6.51%, respectively; P = 0.0096), whereas there were no differences in the proportions of these cells in peripheral blood mononuclear cells (PBMCs) from healthy donors (94.73% ± 1.39% and 93.79% ± 1.08%, respectively; not significant). The CD3ζ+ cell/CD3ε+ cell ratio was also significantly decreased for T cells from the SMs of patients with OA compared with that for T cells from the PBMCs of healthy donors (0.84 ± 0.17 and 0.99 ± 0.01, respectively; P = 0.0302). The proportions of CD3ε+ CD3ζ+ cells were lower in the SMs of patients with OA than in the PBMCs of healthy donors (65.04% ± 6.7% and 90.81% ± 1.99%, respectively; P = 0.0047). Substantial proportions (about 15%) of CD3ε+ CD3ζ-negative (CD3ζ−) and CD3ε-negative (CD3ε−) CD3ζ− cells were found in the SMs of patients with OA. Amplification of the CD3ζ and CD3δ transcripts from the SMs of patients with OA by reverse transcriptase PCR consistently exhibited stronger bands for CD3δ cDNA than for CD3ζ cDNA The CD3ζ/CD3δ transcript ratio in the SMs of patients with OA was significantly lower than that in PBMCs from healthy controls (P < 0.0001). These results were confirmed by competitive MIMIC PCR. Immunoreactivities for the CD3ζ protein were detected in the SMs of 10 of 19 patients with OA, and they were of various intensities, whereas SMs from all patients were CD3ε+ (P = 0.0023). The decreased expression of the CD3ζ transcript and protein in T cells from the SMs of patients with OA relative to that of the CD3ε transcript is suggestive of chronic T-cell stimulation and supports the concept of T-cell involvement in OA.

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Expression of inhibitory receptors on CD4+ and CD8+ T cells from healthy Colombian donors

Universitas Scientiarum ◽

10.11144/javeriana.sc17-1.eoir ◽

2012 ◽

Vol 17 (1) ◽

pp. 35

Author(s):

Alejandra Rico- Lombana Rico- Lombana ◽

Jose Mateus ◽

Paola Lasso ◽

John Mario González ◽

Concepción Judith Puerta ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Mononuclear Cells ◽

Inhibitory Receptors ◽

Peripheral Blood Mononuclear ◽

Programmed Death ◽

Significant Difference ◽

Programmed Death 1

T cell activation involves positive cellular signals that promote effector functions and negative signals that contribute to the regulation of these responses. These regulatory signals are generated upon activation of receptors on T cells that include CD160, 2B4, Programmed Death-1 and CTLA-4. Objective. To evaluate the expression of inhibitory receptors like CD160, 2B4, Programmed Death-1 and CTLA-4 on CD4+ and CD8+ T cells from healthy Colombian donors. Materials and methods. Peripheral blood mononuclear cells from 30 healthy donors from Bogotá (Colombia) were obtained via Ficoll-Hypaque density gradient and cells were stained with specific conjugated antibodies previously titrated. Results. The CD160, 2B4, and Programmed Death-1 inhibitory markers were detected on CD4+ T cells with expression levels of 0.35%, 1.04%, and 1.35%, respectively. On CD8+ T cells, these markers were expressed at higher levels: 16%, 8.97%, and 4.3%, respectively. In contrast to the other receptors, CTLA-4 frequency of expression showed no significant difference between CD4+ (1.56%) and CD8+ (1.53%) T cells. Frequency of CD160/2B4 and CTLA-4/ Programmed Death-1 coexpression was 0.18% and 0.09% on CD4+ cells, and 4.02% and 0.2% on CD8+ T cells. Conclusions. This is the first report showing the frequency of inhibitory receptors such as CD160, 2B4, Programmed Death-1, and CTLA-4 on CD4+ and CD8+ T cells from healthy Colombian donors. Our findings serve as a baseline for the analysis and comparison of these receptors in Colombian populations with different disease conditions. Key words: inhibitory receptors, T cells

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Selection and T-cell antigenicity of synthetic long peptides derived from SARS-CoV-2

Journal of General Virology ◽

10.1099/jgv.0.001698 ◽

2022 ◽

Vol 103 (1) ◽

Author(s):

Katarzyna Piadel ◽

Amin Haybatollahi ◽

Angus George Dalgleish ◽

Peter Lawrence Smith

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

T Cell Responses ◽

Hla Class I ◽

Peripheral Blood Mononuclear ◽

Cell Responses

The pandemic caused by SARS-CoV-2 has led to the successful development of effective vaccines however the prospect of variants of SARS-CoV-2 and future coronavirus outbreaks necessitates the investigation of other vaccine strategies capable of broadening vaccine mediated T-cell responses and potentially providing cross-immunity. In this study the SARS-CoV-2 proteome was assessed for clusters of immunogenic epitopes restricted to diverse human leucocyte antigen. These regions were then assessed for their conservation amongst other coronaviruses representative of different alpha and beta coronavirus genera. Sixteen highly conserved peptides containing numerous HLA class I and II restricted epitopes were synthesized from these regions and assessed in vitro for their antigenicity against T-cells from individuals with previous SARS-CoV-2 infection. Monocyte derived dendritic cells were generated from these peripheral blood mononuclear cells (PBMC), loaded with SARS-CoV-2 peptides, and used to induce autologous CD4+ and CD8+ T cell activation. The SARS-CoV-2 peptides demonstrated antigenicity against the T-cells from individuals with previous SARS-CoV-2 infection indicating that this approach holds promise as a method to activate anti-SAR-CoV-2 T-cell responses from conserved regions of the virus which are not included in vaccines utilising the Spike protein.

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Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58

Blood ◽

10.1182/blood.2020005546 ◽

2020 ◽

Vol 136 (21) ◽

pp. 2437-2441 ◽

Cited By ~ 2

Author(s):

Johanna Veldman ◽

Lydia Visser ◽

Magdalena Huberts-Kregel ◽

Natasja Muller ◽

Bouke Hepkema ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hodgkin Lymphoma ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Immunological Synapse ◽

Class Ii ◽

Rosette Formation ◽

Peripheral Blood Mononuclear

Abstract A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II–matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58.

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Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27

Blood ◽

10.1182/blood-2006-08-041541 ◽

2007 ◽

Vol 110 (7) ◽

pp. 2528-2536 ◽

Cited By ~ 39

Author(s):

Christine Brender ◽

Gillian M. Tannahill ◽

Brendan J. Jenkins ◽

Joel Fletcher ◽

Ruth Columbus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cell Receptor ◽

Striking Similarity ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

Suppressor of cytokine signaling (SOCS) proteins regulate the intensity and duration of cytokine responses. SOCS3 is expressed in peripheral T cells, and recent reports have suggested that overexpression of SOCS3 modulates antigen- and/or costimulation-induced T-cell activation. To study the role of SOCS3 in the regulation of T-cell activation, we used a conditional gene-targeting strategy to generate mice that lack SOCS3 in T/natural killer T cells (Socs3ΔLck/ΔLck mice). SOCS3-deficient CD8 T cells showed greater proliferation than wild-type cells in response to T-cell receptor (TCR) ligation despite normal activation of signaling pathways downstream from TCR or CD28 receptors. Signaling in response to the gp130 cytokines interleukin (IL)–6 and IL-27 was prolonged in Socs3ΔLck/ΔLck T cells, and T cells from gp130Y757F/Y757F mice, in which the SOCS3-binding site on gp130 is ablated, showed a striking similarity to SOCS3-deficient CD8 T cells. Although the proliferative defect of Socs3ΔLck/ΔLck T cells was not rescued in the absence of IL-6, suppression of IL-27 signaling was found to substantially reduce anti-CD3–induced proliferation. We conclude that enhanced responses to TCR ligation by SOCS3-deficient CD8 T cells are not caused by aberrant TCR-signaling pathways but, rather, that increased IL-27 signaling drives unregulated proliferation in the absence of SOCS3.

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Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20201763 ◽

2021 ◽

Vol 218 (7) ◽

Author(s):

Miwa Sasai ◽

Ji Su Ma ◽

Masaaki Okamoto ◽

Kohei Nishino ◽

Hikaru Nagaoka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd8 T Cell ◽

Cell Receptor ◽

Tcr Signaling

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell–dependent adaptive immunity.

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