ANTIBODIES WHICH TARGET THE COMMON CYTOKINE RECEPTOR GAMMA (γc) CHAIN ENHANCE ACTIVATION-INDUCED APOPTOSIS OF ALLOSPECIFIC CD8+ T CELLS

Key Points Monoclonal antibody blockade of the common γ chain attenuates acute and chronic GVHD. Common γ-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.

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CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽

10.1182/blood.v96.1.195.013k51_195_202 ◽

2000 ◽

Vol 96 (1) ◽

pp. 195-202 ◽

Cited By ~ 1

Author(s):

Masaki Tateyama ◽

Naoki Oyaizu ◽

Thomas W. McCloskey ◽

Soe Than ◽

Savita Pahwa

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Interleukin 2 ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Cross Linking ◽

Induced Apoptosis ◽

Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

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Increased CD95/Fas-Induced Apoptosis of HIV-Specific CD8+ T Cells

Immunity ◽

10.1016/s1074-7613(01)00246-1 ◽

2001 ◽

Vol 15 (6) ◽

pp. 871-882 ◽

Cited By ~ 125

Author(s):

Yvonne M Mueller ◽

Stephen C De Rosa ◽

Justin A Hutton ◽

James Witek ◽

Mario Roederer ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Induced Apoptosis

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THE EXPRESSION OF CD11A BUT NOT CD45RA CORRELATES WITH CD95 (FAS/APO-1) EXPRESSION, ENHANCED ACTIVATION INDUCED APOPTOSIS AND CD55 EXPRESSION IN HUMAN CD8 T CELLS

Biochemical Society Transactions ◽

10.1042/bst024619sa ◽

1996 ◽

Vol 24 (4) ◽

pp. 619S-619S

Author(s):

C. Höflich ◽

W.-D. Döcke ◽

H.-D. Volk

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Induced Apoptosis

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The effect of the ratio of CD4 + to CD8 + T-cells on radiation-induced apoptosis in human lymphocyte subpopulations

International Journal of Radiation Biology ◽

10.1080/09553000210144475 ◽

2002 ◽

Vol 78 (8) ◽

pp. 681-688 ◽

Cited By ~ 18

Author(s):

R. C. Wilkins ◽

B. C. Kutzner ◽

M. Truong ◽

J. R. N. McLean

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Human Lymphocyte ◽

Lymphocyte Subpopulations ◽

Radiation Induced ◽

Induced Apoptosis

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In Vitro Evidence That Cytokine Receptor Signals Are Required for Differentiation of Double Positive Thymocytes into Functionally Mature CD8+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021765 ◽

2003 ◽

Vol 197 (4) ◽

pp. 475-487 ◽

Cited By ~ 91

Author(s):

Qing Yu ◽

Batu Erman ◽

Avinash Bhandoola ◽

Susan O. Sharrow ◽

Alfred Singer

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Glucose Transporter ◽

Experimental System ◽

Cytokine Receptor ◽

Cytokine Receptors ◽

Double Positive ◽

Thymocyte Differentiation ◽

Tcr Signals

CD4+8+ double positive (DP) thymocytes differentiate into CD4+ and CD8+ mature T cells in response to TCR signals. However, TCR signals that are initiated in DP thymocytes are unlikely to persist throughout all subsequent differentiation steps, suggesting that other signals must sustain thymocyte differentiation after TCR signaling has ceased. Using an in vitro experimental system, we now demonstrate that cytokine receptor signals, such as those transduced by IL-7 receptors, are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells as they: (a) up-regulate Bcl-2 expression to maintain thymocyte viability; (b) enhance CD4 gene silencing; (c) promote functional maturation;and (d) up-regulate surface expression of glucose transporter molecules, which improve nutrient uptake and increase metabolic activity. IL-7Rs appear to be unique among cytokine receptors in maintaining the viability of newly generated CD4−8+ thymocytes, whereas several different cytokine receptors can provide the trophic/differentiative signals for subsequent CD8+ thymocyte differentiation and maturation. Thus, cytokine receptors provide both survival and trophic/differentiative signals with varying degrees of redundancy that are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells.

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CD8+T Cells in HIV Disease Exhibit Cytokine Receptor Perturbation and Poor T Cell Receptor Activation but Are Responsive to γ‐Chain Cytokine–Driven Proliferation

The Journal of Infectious Diseases ◽

10.1086/500471 ◽

2006 ◽

Vol 193 (6) ◽

pp. 879-887 ◽

Cited By ~ 20

Author(s):

Rajendra Pahwa ◽

Thomas W. McCloskey ◽

Olga C. Aroniadis ◽

Natasa Strbo ◽

Subramaniam Krishnan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Receptor Activation ◽

Cytokine Receptor ◽

Hiv Disease

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Common Gamma Chain Cytokines Contribute To Acute GvHD Via Perforin/Granzyme B-Mediated Cytotoxicity Of CD8 T Cells

Blood ◽

10.1182/blood.v122.21.2015.2015 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2015-2015

Author(s):

Vincent Schwarze ◽

Anne-Kathrin Hechinger ◽

Franziska Leonhardt ◽

Gabriele Prinz ◽

Annette Schmitt-Gräff ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Granzyme B ◽

Allogeneic Transplantation ◽

Gamma Chain ◽

Common Gamma Chain ◽

The Common

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an important treatment option for different hematological malignancies, but also for some nonmalignant hematological disorders such as sickle cell anemia, aplastic anemia or thalassemia(1). In the ladder group the graft-versus-leukemia (GvL) effect mediated by donor T cells is less important and prevention of graft-versus-host disease (GvHD), which occurs in 40-50% of allo-HCT patients, is a major priority. The common gamma chain (CD132) is a cytokine receptor sub-unit that is common to the interleukin (IL) receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Since several of these cytokines were shown to be increased in the serum of patients developing acute GvHD, we reasoned that inhibition of CD132 could have a profound effect on acute GvHD by inhibiting the bioactivity of multiple proinflammatory cytokines. We observed that anti-CD132 treatment reduced GvHD potently with respect to survival, production of TNF, IFN-γ, IL-6, MCP-1 and GvHD histopathology. Protection was only seen when anti-CD132 was applied in a CD8 T cell-dependent GvHD model while no protection was seen when only CD4 T cells were given. Mechanistically, we could show that CD8 T cells isolated from mice treated with anti-CD132 had reduced levels of Granzyme B and that GvHD induced by Perforin-deficient T cells was resistant towards blockade by anti-CD132 treatment. These data indicated a role of the common gamma chain cytokines for the induction of Perforin/Granzyme B in CD8 T cells during GvHD. Compatible with this notion, exposure of CD8 T cells towards IL-2, IL-7, IL-15 and IL-21 alone or in combination induced increased levels of Granzyme B. Based on these findings, we concluded that CD8 T cells that are activated by common gamma chain cytokines during GvHD produce then Granzyme B which can be blocked by anti-CD132 treatment. This therapeutic approach has particular clinical potential for patients undergoing allogeneic transplantation for nonmalignant indications, since graft-versus-tumor activity is not required. Disclosures: No relevant conflicts of interest to declare.

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JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation

Blood ◽

10.1182/blood.2020006075 ◽

2020 ◽

Vol 136 (6) ◽

pp. 657-668 ◽

Cited By ~ 7

Author(s):

Lauren K. Meyer ◽

Katherine C. Verbist ◽

Sabrin Albeituni ◽

Brooks P. Scull ◽

Rachel C. Bassett ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Immune System Activation ◽

Stat Signaling ◽

Induced Apoptosis ◽

Stat Pathway

Abstract Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

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