Activation-induced cell death of self-reactive regulatory T cells drives autoimmunity

Activation of self-reactive T cells is a major driver to autoimmunity and is suppressed by mechanisms of regulation. In a humanized model of autoimmune thyroiditis, we investigated the mechanism underlying break of tolerance. Here, we found that a human TCR specific for the self-antigen thyroid peroxidase (TPO) is positively selected in the thymus of RAG KO mice on both T effector (Teff) and T regulatory (Treg) CD4+Foxp3+cells. In vivo Teffare present in all immune organs, whereas the TPO-specific Tregare present in all lymphoid organs with the exception of the thyroid-draining lymph nodes. We suggest that the presence of TPO in the thyroid draining lymph nodes induces the activation of Teffand the depletion of Tregvia activation-induced cell death (AICD). Our findings provide insights on the failure of the mechanisms of immune tolerance, with potential implications in designing immunotherapeutic strategies.

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Migration and Differentiation of Autoreactive B-1 Cells Induced by Activated γ/δ T Cells in Antierythrocyte Immunoglobulin Transgenic Mice

Journal of Experimental Medicine ◽

10.1084/jem.192.11.1577 ◽

2000 ◽

Vol 192 (11) ◽

pp. 1577-1586 ◽

Cited By ~ 42

Author(s):

Norihiko Watanabe ◽

Koichi Ikuta ◽

Sidonia Fagarasan ◽

Shujiro Yazumi ◽

Tsutomu Chiba ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

The Self ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph ◽

Recombination Activating Gene ◽

T Cell Help ◽

Self Antigen ◽

Antibody Secreting Cells

Using normal and transgenic (Tg) mice, we have shown that peritoneal B-1 cells are activated by administration of cytokines or lipopolysaccharide and migrate to other lymphoid organs where they differentiate into antibody-secreting cells. However, little is known about the process of B-1 cell migration and differentiation in vivo. We developed a mouse line by crossing the antierythrocyte antibody Tg mice (HL mice) with TCR-γ/δ Tg mice specific for a self-thymus leukemia (TL) antigen in the recombination activating gene (RAG)2−/− background. In the presence of the self-antigen, Tg γ/δ T cells increased in number and manifested activated phenotypes. Peritoneal B-1 cells in these mice migrated into mesenteric lymph nodes and differentiated into autoantibody-secreting cells, resulting in strong autoimmune hemolytic anemia. Furthermore, transfer of RAG2−/− × HL bone marrow or peritoneal cells into the peritoneal cavity of RAG2−/− × TCR-γ/δ Tg mice gave rise to donor-derived B-1 cells in mesenteric lymph nodes, and these cells produced the autoantibody. Thus, this study demonstrates that the migration of B-1 cells and differentiation into the antibody-secreting cells can be induced by noncognate T cell help and implies the possibility that γ/δ T cells may induce B-1 cell differentiation in vivo.

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Faculty Opinions recommendation of Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1998956.2932058 ◽

2010 ◽

Author(s):

Mohamed Sayegh ◽

Jessamyn Bagley

Keyword(s):

T Cells ◽

Cell Death ◽

Dendritic Cell ◽

Lymph Nodes ◽

Draining Lymph Nodes

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Faculty Opinions recommendation of Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1998956.1566054 ◽

2010 ◽

Author(s):

Mark Smyth

Keyword(s):

T Cells ◽

Cell Death ◽

Dendritic Cell ◽

Lymph Nodes ◽

Draining Lymph Nodes

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Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes

Blood ◽

10.1182/blood-2007-05-088286 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4285-4292 ◽

Cited By ~ 26

Author(s):

Véronique Mateo ◽

Michael Ménager ◽

Geneviève de Saint-Basile ◽

Marie-Claude Stolzenberg ◽

Bertrand Roquelaure ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Lymphocytes ◽

Peripheral Tolerance ◽

Gene Encoding ◽

Activation Induced Cell Death ◽

Dependent Cell ◽

Lymphoproliferative Syndrome ◽

Dependent Pathway

Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)–dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.

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The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.22.15.5419-5433.2002 ◽

2002 ◽

Vol 22 (15) ◽

pp. 5419-5433 ◽

Cited By ~ 109

Author(s):

Susanne M. A. Lens ◽

Takao Kataoka ◽

Karen A. Fortner ◽

Antoine Tinel ◽

Isabel Ferrero ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Death Receptor ◽

Cell Receptor ◽

Caspase 8 ◽

Activation Induced Cell Death

ABSTRACT The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4− CD8− T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

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Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer

Blood ◽

10.1182/blood-2004-11-4390 ◽

2005 ◽

Vol 106 (2) ◽

pp. 617-625 ◽

Cited By ~ 58

Author(s):

Sven Baumann ◽

Anja Dostert ◽

Natalia Novac ◽

Anton Bauer ◽

Wolfgang Schmid ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Glucocorticoid Receptor ◽

Fas Ligand ◽

Regulatory Elements ◽

Activated T Cells ◽

Activation Induced Cell Death

Abstract Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs. (Blood. 2005;106:617-625)

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T Cells Derived From Human Melanoma Draining Lymph Nodes Mediate Melanoma-specific Antitumor Responses In Vitro and In Vivo in Human Melanoma Xenograft Model

Journal of Immunotherapy ◽

10.1097/cji.0000000000000078 ◽

2015 ◽

Vol 38 (6) ◽

pp. 229-238 ◽

Cited By ~ 4

Author(s):

Mei Zhang ◽

Hallie Graor ◽

Anthony Visioni ◽

Madeleine Strohl ◽

Lu Yan ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Xenograft Model ◽

Human Melanoma ◽

Human Melanoma Xenograft ◽

Melanoma Xenograft ◽

Draining Lymph Nodes

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Foxp3+ T Cells Induce Perforin-Dependent Dendritic Cell Death in Tumor-Draining Lymph Nodes

Immunity ◽

10.1016/j.immuni.2009.11.015 ◽

2010 ◽

Vol 32 (2) ◽

pp. 266-278 ◽

Cited By ~ 107

Author(s):

Alexandre Boissonnas ◽

Alix Scholer-Dahirel ◽

Virginie Simon-Blancal ◽

Luigia Pace ◽

Fabien Valet ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Dendritic Cell ◽

Lymph Nodes ◽

Draining Lymph Nodes

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PSMA-Specific Car-Engineered T Cells for Prostate Cancer: CD28 outperforms combined CD28-41BB “Super- stimulation”

10.20944/preprints202007.0520.v1 ◽

2020 ◽

Author(s):

Gaia Zuccolotto ◽

Alessandro Penna ◽

Giulio Fracasso ◽

Isabella Monia Montagner ◽

Debora Carpanese ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Cell Death ◽

Antiangiogenic Effect ◽

Car T Cells ◽

Activation Induced Cell Death ◽

Car T ◽

Minimum Number ◽

Signaling Domains

Despite advances in the understanding of its molecular pathophysiology, prostate cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate specific membrane antigen (PSMA), a glycoprotein that is overexpressed in prostate cancer, which expression involves neovasculature of several tumor entities, thus envisaging an additional antiangiogenic effect. To optimize the CAR design, we compared two CARs with signaling domains containing one or two T cell costimulatory elements, in addition to CD3ζ. Conversely, what has been described for other CARs, a third-generation CAR (containing CD28 and 41BB co-signaling domains) induced a potent antitumor effect similar to a second-generation CAR (containing CD28 co-signaling domain), though we observed a detrimental effect of the additional costimulatory domain that was attributed to increased activation-induced cell death (AICD). This “super-stimulation” resulted in exhaustion of cells, higher frequencies of cell death and, more importantly, the impossibility of sufficiently expanding the CAR cells to obtain the minimum number of cells requested for in vivo therapies. While the superiority of 2nd and 3rd generation over 1st generation CAR T cells has been clearly shown in both preclinical and clinical studies, the optimal combination of costimulatory domains for 3rd generation CAR-T cells must still be defined and should be evaluated case-by-case in order to fine-tune immunotherapy approaches.

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