Cytotoxicity against lymphoblastoid cells mediated by a T-cell clone from an aplastic anaemia patient: role of CD59 on target cells

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

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Concomitant eosinophilia, fasciitis, and mycosis fungoides-like reaction with antinuclear autoantibodies in chronic myeloid leukaemia: role of a T-cell clone induced by imatinib

The Lancet Oncology ◽

10.1016/s1470-2045(05)70322-3 ◽

2005 ◽

Vol 6 (9) ◽

pp. 728-729 ◽

Cited By ~ 6

Author(s):

Fabrice Jardin ◽

Philippe Courville ◽

Pascal Lenain ◽

Sophie Pouplin ◽

Nathalie Contentin ◽

...

Keyword(s):

T Cell ◽

Chronic Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Mycosis Fungoides ◽

Cell Clone ◽

Antinuclear Autoantibodies ◽

T Cell Clone

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The natural killer-related receptor for HLA-C expressed on T cells from CD3+ lymphoproliferative disease of granular lymphocytes displays either inhibitory or stimulatory function

Blood ◽

10.1182/blood.v87.6.2369.bloodjournal8762369 ◽

1996 ◽

Vol 87 (6) ◽

pp. 2369-2375 ◽

Cited By ~ 22

Author(s):

A Cambiaggi ◽

AM Orengo ◽

R Meazza ◽

S Sforzini ◽

PL Tazzari ◽

...

Keyword(s):

T Cell ◽

Natural Killer ◽

Cell Line ◽

Cell Clone ◽

Molecular Form ◽

Lymphoproliferative Disease ◽

Cytolytic Activity ◽

Target Cells ◽

T Cell Clone ◽

Granular Lymphocytes

Four patients with lymphoproliferative disease of granular lymphocytes (LDGL) coexpressing CD3 and the natural killer (NK)-related “p58” receptor for HLA-C alleles were studied. These CD3+p58+ LDGLs have been detected among a series of 44 CD3+ LDGLs analyzed. Two patients with LDGL (GI and BA) expressed only the p58 molecule defined by the GL-183 and CH-L monoclonal antibodies (MoAbs), while the cases of patients PU and MA also coexpressed the molecular form identified by EB6 anti-p58 MoAb. Three LDGL cases (GI, MA, and PU) displayed the CD8+4-CD16+ T- cell receptor (TCR)alpha/beta+ phenotype, while one patient (BA) was CD8+4+CD16+ TCRalpha/beta+. Freshly isolated granular lymphocytes (GL) from these cases displayed cytolytic activity in an anti-CD3 MoAb- triggered redirected killing assay against the Fcgamma-receptor+ (Fcgamma-R+) P815 target cell line. Lysis of P815 target cells, triggered by an anti-CD3 or by anti-CD16 MoAb, could be inhibited by the addition of anti-p58 MoAb in three fresh or interleukin (IL)-2- cultured GL tested (GI, MA, and PU). Triggering of cytotoxicity against the HLA-DR+ Fcgamma-R+ Daudi cell line induced by appropriate superantigens could also be inhibited by anti-p58 MoAb in patients PU and GI with LDGL. These data indicate that activation through the CD16, CD3, and TCR molecules can be modulated by p58 receptors in these LDGLs. On the contrary, IL-2-expanded cells of patient BA were induced to lyse P815 target cells by anti-p58 MoAb. In addition, anti-p58 MoAB enhanced anti-CD16 MoAb triggered lysis and did not inhibit activation via CD3. These data indicate that, in this particular patient with LDGL, p58 displays a stimulatory effect on cell triggering, rather than the typical inhibitory effect previously observed in p58+ T-cell clones derived from healthy donors. The anti-p58 MoAb did not induce CA++ mobilization in p58+ LDGLs and in a p58+CD3+ normal T-cell clone equipped with inhibitory p58 molecules, while Ca++ mobilization could be observed in cultured GL from patient BA, which could be activated by anti-58 MoAb. These findings suggest that stimulatory and inhibitory p58 molecules are equipped with different signal transducing properties, thus contributing to a better knowledge of the normal counterpart.

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Nitrendipine-induced inhibition of calcium influx in a human T-cell clone: Role of cell depolarization

Cell Calcium ◽

10.1016/0143-4160(91)90005-y ◽

1991 ◽

Vol 12 (4) ◽

pp. 313-323 ◽

Cited By ~ 26

Author(s):

C Randriamampita

Keyword(s):

T Cell ◽

Calcium Influx ◽

Cell Clone ◽

Human T Cell ◽

T Cell Clone ◽

Cell Depolarization

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An Ovalbumin Peptide-Specific Cytotoxic T Cell Clone with Antigen Self-Presentation Capacity Uses Two Distinct Mechanisms to Kill Target Cells

Cellular Immunology ◽

10.1006/cimm.1993.1295 ◽

1993 ◽

Vol 152 (2) ◽

pp. 333-347 ◽

Cited By ~ 5

Author(s):

Thomas Dick ◽

Gabi Reichmann ◽

Klaus Ebnet ◽

Markus M. Simon ◽

Hans-Peter Dienes ◽

...

Keyword(s):

T Cell ◽

Cell Clone ◽

Cytotoxic T Cell ◽

Target Cells ◽

Self Presentation ◽

T Cell Clone

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A clone-specific monoclonal antibody that inhibits cytolysis of a cytolytic T cell clone.

Journal of Experimental Medicine ◽

10.1084/jem.157.3.921 ◽

1983 ◽

Vol 157 (3) ◽

pp. 921-935 ◽

Cited By ~ 41

Author(s):

D W Lancki ◽

M I Lorber ◽

M R Loken ◽

F W Fitch

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Bone Marrow Cells ◽

Cytotoxic T Lymphocyte ◽

Cell Clone ◽

Lymphocyte Culture ◽

Cytolytic Activity ◽

Target Cells ◽

Region Gene ◽

T Cell Clone

Monoclonal antibody 384.5 specifically inhibited cytolysis of P-815 target cells by cloned L3 cytotoxic T lymphocyte (CTL) effector cells. The lytic activity of other cloned CTL that have other distinct specificities was not affected. Antibody 384.5 did not inhibit the cytolytic activity of bulk populations of C57BL/6 mixed lymphocyte culture (MLC) cells. Concanavalin A-facilitated cytolysis by T cell clone L3 but not T cell clone B18 was inhibited by antibody 384.5, whereas phytohemagglutinin-facilitated cytolysis by L3 cells was not strongly inhibited. Antibody 384.5 binds specifically to L3 cells but not to several other T lymphocytes clones, or to a detectable portion of populations of primary MLC cells, normal spleen, thymus, lymph node, or bone marrow cells. In contrast, C57BL/6 anti-B10.A(5R) secondary MLC cells (genetically enriched for reactivity against the H-2Dd region gene products) contained a small population which reacted with the antibody 384.5. The determinant detected by antibody 384.5 was susceptible to trypsin treatment, and was reexpressed after overnight incubation. These results suggest that the monoclonal antibody 384.5 detects an endogenously synthesized clone-specific determinant associated with the cytolytic activity of the L3 CTL clone. These properties make antibody 384.5 an attractive candidate for an antibody that reacts with the antigen-recognition site of a cytolytic T cell antigen receptor.

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Characterization of MHC Class-I Restricted TCRαβ+CD4−CD8− Double-Negative T Cells Recognizing the gp100 Antigen from a Melanoma Patient after gp100 Vaccination

Blood ◽

10.1182/blood.v112.11.4905.4905 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4905-4905

Author(s):

Simon Voelkl ◽

Tamson Moore ◽

Michael Rehli ◽

Michael Nishimura ◽

Karin Fischer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class I ◽

Peripheral Blood ◽

Melanoma Patient ◽

Cell Clone ◽

Class I ◽

Target Cells ◽

Double Negative ◽

T Cell Clone

Abstract The immune attack against malignant tumors requires the concerted action of CD8+ cytotoxic T lymphocytes (CTL) as well as CD4+ T helper cells. The contribution of T cell receptor (TCR)αβ+ CD4− CD8− double-negative (DN) T cells to anti-tumor immune responses is widely unknown. In previous studies, we have demonstrated that DN T cells with a broad TCR repertoire are present in humans in the peripheral blood and the lymph nodes of healthy individuals. Here we characterize a human DN T cell clone (T4H2) recognizing an HLA-A2-restricted melanoma-associated antigenic gp100-peptide isolated from the peripheral blood of a melanoma patient. Antigen recognition by the T4H2 DN clone resulted in specific secretion of IFN-γ and TNF. Although lacking the CD8 molecule the gp100-specifc DN T cell clone was able to confer antigen-specific cytotoxicity against gp100-loaded target cells as well as HLA-A2+ gp100 expressing melanoma cells. The cytotoxic capacity was found to be perforin/granzymeB-dependent. Together, these data indicate that functionally active antigen-specific DN T cells recognizing MHC class I-restricted tumor-associated antigen (TAA) may contribute to anti-tumor immunity in vivo.

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Distinct Regulation of T-Cell Death by CD28 Depending on Both Its Aggregation and T-Cell Receptor Triggering: A Role for Fas-FasL

Blood ◽

10.1182/blood.v92.4.1350.416k24_1350_1363 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1350-1363 ◽

Cited By ~ 2

Author(s):

Y. Collette ◽

A. Benziane ◽

D. Razanajaona ◽

D. Olive

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Cell Clone ◽

Cell Receptor ◽

Fasl Expression ◽

T Cell Clone ◽

Induced Apoptosis

CD28 is a major coreceptor that regulates cell proliferation, anergy, and viability of T cells. The negative selection by T-cell receptor (TCR)-induced cell death of immature thymocytes as well as of activated human antigen-specific T-cell clone, requires a costimulatory signal that can be provided by CD28. Conversely, CD28-mediated signals increase expression of Bcl-XL, a survival gene, and promote survival of naive T cells cultured in the absence of antigen or costimulation. Because CD28 appears to both protect from, or induce T-cell death, one important question is to define the activation and cellular parameters that dictate the differential role of CD28 in T-cell apoptosis. Here, we compared different CD28 ligands for their ability to regulate TCR-induced cell death of a murine T-cell hybridoma. In these cells, TCR triggering induced expression of Fas and FasL, and cell death was prevented by anti-Fas blocking monoclonal antibody (MoAb). When provided as a costimulus, both CD28 MoAb and the B7.1 and B7.2 counter receptors downregulated, yet did not completely abolish T-cell receptor–induced apoptosis. This CD28 cosignal resulted in both upregulation of Bcl-XL and prevention of FasL expression. In marked contrast, when given as a single signal, CD28 MoAb or B7.1 and B7.2 induced FasL expression and resulted in T-cell death by apoptosis, which was dependent on the level of CD28 ligation. Furthermore, triggering of CD28 upregulated FasL and induced a marked T-cell death of previously activated normal peripheral T cells. Our results identify Fas and FasL as crucial targets of CD28 in T-cell death regulation and show that within the same cell population, depending on its engagement as a single signal or as a costimulus together with the TCR, CD28 can either induce a dose-dependent death signal or protect from cell death, respectively. These data provide important insights into the role of CD28 in T-cell homeostasis and its possible implication in neoplastic disorders. © 1998 by The American Society of Hematology.

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Development of a novel T-cell immunotherapy targeting HEATR1.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.149 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 149-149

Author(s):

Robson Grando Dossa ◽

Tanya Cunningham ◽

Marie Bleakley

Keyword(s):

T Cells ◽

T Cell ◽

Lentiviral Vector ◽

Cell Clone ◽

Cell Receptor ◽

Target Cells ◽

Normal Donor ◽

Hematopoietic Stem ◽

T Cell Clone ◽

Leukemic Relapse

149 Background: Allogeneic hematopoietic stem cell transplantation (HCT) often cures acute leukemia. However leukemic relapse remains a major cause of HCT failure, and patients with post-HCT relapse have a very poor prognosis. We are developing T cell immunotherapies targeting leukemia-associated minor histocompatibility (H) antigens to manage post-HCT relapse. Because the presentation of minor H antigens is HLA-restricted, a panel of hematopoietic-restricted, leukemia-associated minor H antigens is required to enable the development of broadly applicable minor H antigen targeted immunotherapy. We previously discovered a HLA- B*0801-restricted, leukemia-associated minor H antigen, HEATR1. We showed that HEATR1-specific T cells can specifically kill leukemic blasts and prevent engraftment in a murine model, implying that this minor H antigen is expressed in leukemic stem cells. We have now developed immunotherapy targeting HEATR1 using genetically modified T cells. Methods: We isolated a HEATR1-specific T cell clone from the peripheral blood of a normal donor and sequenced its T cell receptor (TCR). The TCR was codon-optimized and cysteine-modified to maximize expression in T cells and reduce the risk of mispairing with endogenous TCR chains, then cloned into a multicistronic lentiviral vector (LV). Primary CD8+T cells were transduced with the HEATR1 TCR LV and evaluated with a range of assays. Results: The HEATR1-specific T cell clone specifically killed B8+ HEATR1+ primary leukemia. Similarly, CD8+ HEATR1 TCR-transduced T cells killed target cells pulsed with HEATR1 peptide (ISKERAEAL), but not the allelic variant control peptide (ISKERAGAL), and specifically killed cell lines that endogenously present the HEATR1 minor H antigen. HEATR1-transduced T cells also secrete cytokines and proliferate in response to HEATR1+ but not HEATR1-cells. Conclusions: We have demonstrated that HEATR1-specific T cell clone and HEATR1 TCR-transduced T cells can kill HEATR1+ cells. If the safety and efficacy of HEATR1 TCR immunotherapy is confirmed in further preclinical studies, development of phase I clinical studies will be warranted and may ultimately provide a new option for management of relapse after HCT.

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