scholarly journals 235 Novel biparatopic TIM-3 antibody effectively blocks multiple inherent ligands and activates anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A251-A251
Author(s):  
Yuji Mishima ◽  
Kanto Nakajima ◽  
Mamoru Shiraishi ◽  
Haruka Matsumura ◽  
Takahiko Aramaki ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Regression ◽  
Apoptotic Cell ◽  
Phage Display Libraries ◽  
Lymph Node Cells ◽  
Multiple Ligands

BackgroundT cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is a part of modules expressed on dysfunctional or exhausted T cells as well as dendritic cells and has emerged as a target for several therapeutic antibodies that are under clinical development. Co-blockade of TIM-3 and PD-1 results in tumor regression in preclinical models and improves anticancer T cell responses in patients with advanced cancers. TIM-3 has been reported to have multiple ligands including galectin-9, phosphatidylserine, CEACAM-1 and HMGB1, which bind to different regions on the extracellular domain of TIM-3. Most of the TIM-3 antibodies developed to date are intended to inhibit phosphatidylserine that binds to the pocket in TIM-3 immunoglobulin V domain. Galectin-9 binds to carbohydrate motifs on the opposite side of phosphatidylserine-binding site in immunoglobulin V domain and thereby induces cell death in TIM-3+ T cells. We report herein novel antibodies that block TIM-3 binding to multiple ligands including these two important ligands simultaneously.MethodsAnti-TIM-3 antibodies were generated by immunizing mice with a purified recombinant TIM-3 protein and TIM-3-expressing mammalian cell line. Phage display libraries were constructed using cDNAs of splenocytes and lymph node cells of the immunized mice, then subjected to the biopanning using recombinant TIM-3 proteins. After analyzing specificities and affinities to the TIM-3 protein, scFvs obtained were classified by epitope bin and inhibitory effects on TIM-3 binding to the multiple ligands. The scFvs were converted to scFv-Fc to generate biparatopic (bispecific) antibodies.ResultsAt least five classes of TIM-3 antibodies were obtained, and each class was grouped into different epitope bins and has unique inhibitory profiles for multiple ligands of TIM-3. Their biparatopic (bispecific) forms were produced from the scFv clones and subjected to the analyses of TIM-3 binding, inhibition of ligand binding, and immune activation. As expected, the biparatopic antibodies that recognize two different epitopes showed higher affinity and specificity to TIM-3 than monospecific forms. A lead biparatopic antibody that block the binding of TIM-3 to galectin-9 and phosphatidylserine showed remarkable potency on T cell activation, protection from exhaustion and apoptotic cell death of T cells as well as more potent anti-tumor efficacy.ConclusionsThis study demonstrates the successful development of a novel biparatopic antibody that blocks the binding of TIM-3 to phosphatidylserine and galectin-9 simultaneously. The antibody shows the advantages over conventional TIM-3 antibodies in reducing T cell exhaustion and potentially manipulated for the development of human monoclonal antibodies for therapeutic treatment of cancer.

scholarly journals CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.

1996 ◽  
Vol 183 (6) ◽  
pp. 2533-2540 ◽  
Author(s):  
M F Krummel ◽  
J P Allison
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Apoptotic Cell ◽  
Activated T Cells ◽  
Activated State

While interactions between CD28 and members of the B7 family costimulate and enhance T cell responses, recent evidence indicates that the CD28 homologue CTLA-4 plays a downregulatory role. The mechanism by which this occurs is not clear, but it has been suggested that CTLA-4 terminates ongoing responses of activated T cells, perhaps by induction of apoptosis. Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28. This inhibition is not a result of enhanced cell death. Rather it appears to result from restriction of transition from the G1 to the S phase of the cell cycle. Our observation that upregulation of both the IL-2R alpha chain and the CD69 activation antigen are inhibited by CTLA-4 engagement supplies further evidence that CTLA-4 restricts the progression of T cells to an activated state. Together this data demonstrates that CTLA-4 can regulate T cell activation in the absence of induction of apoptotic cell death.

Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

CD4+ T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis

2020 ◽  
Vol 5 (54) ◽  
pp. eabc6373
Author(s):  
Qing Zhao ◽  
Lennard W. Duck ◽  
Fengyuan Huang ◽  
Katie L. Alexander ◽  
Craig L. Maynard ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Formation ◽  
Metabolic Inhibition ◽  
T Cell Epitopes ◽  
Specific Memory

Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell–driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM cell formation upon initial antigen encounter, and ablate existing TM cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4+ T cells after ablation. Microbiota flagellin–specific CD4+ T cells from patients with Crohn’s disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4+ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4+ TM cells and to induce T regulatory (Treg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.

Prostate Cancer Immunology: Biology, Therapeutics, and Challenges

2005 ◽  
Vol 23 (32) ◽  
pp. 8262-8269 ◽  
Author(s):  
W. Scott Webster ◽  
Eric J. Small ◽  
Brian I. Rini ◽  
Eugene D. Kwon
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Advanced Prostate Cancer ◽  
Cell Activation ◽  
Tumor Regression ◽  
Prostate Cancer Treatment ◽  
Mechanistic Basis ◽  
Antigen Presenting

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

Fas- and Fas Ligand Rather Than Perforin-Mediated Apoptosis Has a Dominant Role in Target Cell Death in Murine Models of Immune- Mediated Bone Marrow Failure

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1039-1039
Author(s):  
Jichun Chen ◽  
Stephanie O. Omokaro ◽  
Annahita K. Sarcon ◽  
Neal Young
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Aplastic Anemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Fas Ligand ◽  
Wild Type ◽  
Cell Destruction ◽  
Immune Mediated

Abstract Fas-Fas ligand and perforin-granzyme are two important cell death pathways associated with cytotoxic T cell induced target cell apoptosis. In patients with immune-mediated aplastic anemia, the development of bone marrow (BM) failure is associated with up-regulation in Fas ligand expression on effector cytotoxic T cells and elevated Fas expression on target BM cells. In some aplastic anemia patients, peripheral blood T lymphocytes also carry polymorphisms in the perforin gene which have been associated with familial hemophagocytosis. These findings suggested that Fas ligand/Fas might be the key signaling molecules mediating cell destruction while perforin might also play a role in the development of BM failure in patients with aplastic anemia. We have modeled immune-mediated BM failure in the mouse by infusing allogeneic lymph node (LN) cells from C57BL/6 (B6) donors into sublethally-irradiated CByB6F1 and C.B10 recipients that are mismatched at either major histocompatibility (MHC) or minor histocompatibility (minor-H) loci. Expansion and activation of allogeneic T cells results in increased production of the inflammatory cytokines gamma interferon and tissue necrosis factor alpha in recipient BM, massive BM cell destruction, severe marrow hypoplasia, and fatal pancytopenia. In the current study, we directly tested the roles of Fas, Fas ligand and perforin in the development of BM failure by using murine models with spontaneous mutations at the lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) loci, or with germline deletion of the gene perforin (prf−/−). Fas and Fas ligand-deficient lpr and gld mutant mice had no evidence of hematopoietic deficiency despite their autoimmune environment and marked lymphoproliferation. LN cells from lpr and gld mice caused significantly less apoptosis to minor-H mismatched C.B10 BM cells when co-cultured in a cytotoxicity assay in vitro, in comparison to LN cells from wild-type B6 mice. Infusion of lpr, gld, and B6 donor LN cells into sub-lethally irradiated CB10 recipients all caused massive T cell expansion in recipient BM with high level expression of CD11a, indicative of T cell activation, but only B6 LN cells caused severe BM destruction. In contrast, recipients of lpr and gld LN cells had only mild to moderate pancytopenia and marrow hypocellularity. We inferred from these results that disruption of the Fas ligand/Fas signaling pathway effectively abrogated immune mediated marrow destruction. To test the role of perforin in BM failure, we first analyzed prf−/−- mice and found no obvious change in cellular composition in lymphohematopoietic tissues in comparison to wild-type B6 controls. LN cells from prf−/− mice showed reduced ability to induce C.B10 BM cell apoptosis in an in vitro cytotoxicity assay when compared to wild-type B6 LN cells. Infusion of 5–10 million prf−/− LN cells into CByB6F1 and C.B10 recipients produced obvious BM failure in both recipient types with pancytopenia and marrow hypoplasia about 80–90% as severe as in control recipients of 5 million B6 LN cells. In both CByB6F1 and C.B10 recipients, infused prf−/− LN cells resulted in less T cell expansion, a similar level of T cell activation, higher proportions of T cells containing gamma-interferon and tissue necrosis factor-alpha, and a higher proportion of T cells expressing the Fas ligand CD178, in comparison to the infused B6 LN cells. We conclude that Fas-Fas ligand-mediated transmembrane signaling provides the major cell death pathway, while perforin-granzyme-mediated exocytosis plays a minor role, in BM cell destruction in animal models of immune-mediated BM failure.

scholarly journals Simian Immunodeficiency Virus Nef Protein Delays the Progression of CD4+ T Cells through G1/S Phase of the Cell Cycle

2002 ◽  
Vol 76 (8) ◽  
pp. 3587-3595 ◽  
Author(s):  
Thomas Ndolo ◽  
Navdeep K. Dhillon ◽  
Hau Nguyen ◽  
Moraima Guadalupe ◽  
Maria Mudryj ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
T Cell Activation ◽  
Cell Activation ◽  
Apoptotic Cell ◽  
S Phase ◽  
Immunodeficiency Virus

ABSTRACT Human and simian immunodeficiency virus (HIV and SIV, respectively) infections are characterized by gradual depletion of CD4+ T cells. The underlying mechanisms of CD4+ T-cell depletion and HIV and SIV persistence are not fully determined. The Nef protein is expressed early in infection and is necessary for pathogenesis. Nef can cause T-cell activation and downmodulates cell surface signaling molecules. However, the effect of Nef on the cell cycle has not been well characterized. To determine the role of Nef in the cell cycle, we investigated whether the SIV Nef protein can modulate cell proliferation and apoptosis in CD4+ Jurkat T cells. We developed a CD4+ Jurkat T-cell line that stably expresses SIV Nef under the control of an inducible promoter. Alterations in cell proliferation were determined by flow cytometry using stable intracytoplasmic fluorescent dye 5- and 6-carboxyfluorescein diacetate succinimidyl ester and bromodeoxyuridine incorporation. Apoptotic cell death was measured by annexin V and propidium iodide staining. Our results demonstrated that SIV Nef inhibited Fas-induced apoptosis in these cells and that the mechanism involved upregulation of the Bcl-2 protein. SIV Nef suppressed CD4+ T-cell proliferation by inhibiting the progression of cells into S phase of the cell cycle. Suppression involved an upregulation of cyclin-dependent kinase inhibitors p21 and p27 and the downregulation of cyclin D1 and cyclin A. In summary, inhibition of apoptosis by Nef can lead to persistence of infected cells and can support viral replication. In addition, a Nef-mediated delay in cell cycle progression may contribute to CD4+ T-cell anergy/depletion seen in HIV and SIV disease.

scholarly journals Development of a CD123xCD3 Bispecific Antibody (JNJ-63709178) for the Treatment of Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2824-2824 ◽  
Author(s):  
François Gaudet ◽  
Jennifer F Nemeth ◽  
Ronan McDaid ◽  
Yingzhe Li ◽  
Benjamin Harman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Stock Options ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Tumor Regression

Abstract AML is a cancer of the myeloid lineage that is characterized by the accumulation of abnormal white blood cells in the bone marrow and blood. Existing therapies do not lead to cures, partially due to their inability to eliminate residual leukemic stem cells (LSCs) in the bone marrow. T-cell redirection has been shown to be an effective method of treatment for hematologic malignancies (eg, blinatumomab) and represents an attractive approach to treat AML. CD123 (α-chain of the interleukin-3 receptor) has been shown to be expressed on the surface of AML blasts and LSCs. To eradicate CD123+ cells, we developed a bispecific antibody (JNJ-63709178) using the Genmab DuoBody® technology that can bind both CD123 on tumor cells and CD3 on T cells. JNJ-63709178 is a humanized IgG4 bispecific antibody with silenced Fc function. This antibody is able to recruit T cells to CD123-expressing tumor cells and induce the killing of these tumor cells in vitro (MOLM-13, OCI-AML5 and KG-1; EC50 = 0.51-0.91 nM). In contrast, this antibody does not kill CD123- cell lines, demonstrating the specificity of cytotoxicity. Consistently, the degree of cell killing correlated with the level of T-cell activation (CD69 and CD25) and cytokine release (TGF-β and TNF-α). Control bispecific antibodies containing a null arm (viral epitope) paired with a CD123 arm (CD123xnull) or a CD3 arm (nullxCD3) did not induce cytotoxicity or T-cell activation in the assays tested. JNJ-63709178 had no effect on T-cell activation when incubated with T cells alone. In AML murine xenograft models, JNJ-63709178 was able to suppress tumor growth and induce tumor regression (MOLM-13 and KG-1, respectively) in the presence of human peripheral blood mononuclear cells (PBMCs) or T cells. Tumor regression correlated with the infiltration of T cells in the tumor and the expression of T-cell activation markers such as CD25, PD1 and TIM3. Furthermore, this antibody was able to induce the killing of primary CD123+ cancer cells from the blood of patients with AML without the need to supplement with fresh T cells (EC50 = 0.83 nM). These results indicate that JNJ-63709178 can potently and specifically kill CD123+ cancer cells in vitro, in vivo and ex vivo. Pharmacokinetic studies in cynomolgus monkeys support twice weekly dosing for human studies. JNJ-63709178 is currently being investigated in a Phase 1 clinical trial in relapsed and refractory AML (ClinicalTrials.gov ID: NCT02715011). Disclosures Gaudet: Janssen Pharmaceuticals R&D: Employment, Other: Stock options, Patents & Royalties: pending, not yet issued. Nemeth:Janssen Pharmaceuticals R&D: Employment, Other: stock, Patents & Royalties: patent pending. McDaid:Janssen Pharmaceuticals Research and Development: Employment. Li:Janssen: Employment. Harman:Janssen Pharmaceuticals R&D: Employment. Millar:Janssen Pharmaceuticals R&D: Employment, Other: stock options. Teplyakov:Janssen Pharmaceuticals R&D: Employment. Wheeler:Janssen Pharmaceuticals R&D: Employment. Luo:Janssen Pharmaceuticals R&D: Employment. Tam:Janssen Pharmaceuticals R&D: Employment, Other: stocks, Research Funding. Wu:Janssen Pharmaceuticals R&D: Employment. Chen:Janssen Pharmaceuticals R&D: Employment. Rudnick:Janssen Pharmaceuticals R&D: Employment. Chu:Janssen Pharmaceuticals R&D: Employment. Hughes:Janssen Pharmaceuticals R&D: Employment. Luistro:Janssen: Employment. Chin:Janssen: Employment. Babich:Janssen: Employment. Kalota:Janssen Pharmaceuticals R&D: Employment, Other: stock. Singh:Janssen Pharmaceuticals R&D: Employment, Other: stock options. Salvati:Janssen Pharmaceuticals R&D: Employment, Other: stock options, Patents & Royalties: patent. Elsayed:Janssen: Employment, Other: stock options. Attar:Janssen: Employment.

scholarly journals The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy

ESMO Open ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. e000544 ◽  
Author(s):  
Cinzia Solinas ◽  
Chunyan Gu-Trantien ◽  
Karen Willard-Gallo
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Activated T Cells

Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.

Interleukin-6 (IL-6) Prevents Activation-Induced Cell Death: IL-2–Independent Inhibition of Fas/fasL Expression and Cell Death

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4212-4219 ◽  
Author(s):  
Emira Ayroldi ◽  
Ornella Zollo ◽  
Lorenza Cannarile ◽  
Francesca D’ Adamio ◽  
Ursula Grohmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
General Mechanism ◽  
Activation Induced Cell Death ◽  
Induced Apoptosis

Abstract Triggering of the TCR/CD3 complex with specific antigen or anti-CD3 monoclonal antibody initiates activation-induced cell death (AICD) in mature T cells, an effect also mediated by the Fas/FasL system. We have previously shown that CD2 stimulation rescues T cells from TCR/CD3-induced apoptosis by decreasing the expression of Fas and FasL. In the present study, we examined whether the endogenous production of IL-2 plays a role in the effects mediated by CD2 triggering. The results indicated that transcription of Fas/FasL is controlled by interleukin-2 (IL-2) production and that CD2 triggering rescues a T-cell hybridoma from AICD via decreased production of IL-2. To ascertain whether modulation of IL-2 may be a general mechanism of AICD control, we examined other stimuli, capable of modulating the expression of the Fas/FasL system and the ensuing AICD, for ability to affect production of IL-2. We found that IL-6 reduced the level of TCR/CD3-induced apoptosis and the expression of Fas/FasL, yet failed to inhibit IL-2 production. Because IL-2 is involved in both apoptosis and activation events, these results indicate that, in contrast to CD2, which inhibits apoptosis and T cell activation, IL-6 inhibits apoptosis but not IL-2–induced activation. These observations may provide the basis for differential control of T-cell activation and apoptosis.

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