title: T cell sensitivity to HLA class I-mediated apoptosis is dependent on interleukin-2 and interleukin-4.
abstract: Antibody interaction with a specific epitope of the HLA class I alpha1 domain triggers apoptosis of activated but not resting T and B cells by a pathway which involves neither Fas ligand nor tumor necrosis factor-alpha. We have investigated at which stage of activation and proliferation T cells become sensitive to HLA class I-mediated apoptosis, using two monoclonal antibodies (mAb) which recognize the same monomorphic epitope of the HLA class I alpha1 domain (mAb9O, mouse IgG1, and YTH862, rat IgG2b) and can induce apoptosis of phytohemagglutinin (PHA)-activated peripheral blood lymphocytes. Sensitivity to apoptosis develops after the expression of G1 markers (CD69 expression) but it is accelerated by addition of recombinant interleukin-2 (rIL-2). Blocking the IL-2 pathway by cyclosporin A, FK506, rapamycin, anti-IL-2 or CD25 antibodies, prevented the development of sensitivity to apoptosis. Addition of IL-2 and, to a lesser extent, IL-4, reversed the inhibitory effect of cyclosporin A. Conversely, rIL-7 and recombinant interferon-gamma restored proliferation of peripheral blood lymphocytes stimulated by PHA in the presence of cyclosporin A but did not restore sensitivity to class I-mediated apoptosis. Finally cells stimulated in the presence of the DNA polymerase inhibitor aphidicolin did not enter into S phase of the cell cycle but secreted IL-2 and underwent apoptosis when exposed to mAb90 or YTH862. Together, the data indicate that sensitivity of peripheral T cells to HLA class I-mediated apoptosis depends on both activation signals and IL-2 or IL-4, but does not require cell proliferation. These data suggest that YTH862 and mAb90 might be used for achieving clonal deletion of antigen-activated peripheral T cells in vivo, provided that the IL-2 pathway is not blocked by other immunosuppressive agents.
authors.affiliation: Laboratory of Immunology, INSERM U80 UCBL, Hôpital E. Herriot, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Genestier
authors.forename: R
authors.initials: R
authors.lastname: Paillot
authors.forename: N
authors.initials: N
authors.lastname: Bonnefoy-Berard
authors.forename: H
authors.initials: H
authors.lastname: Waldmann
authors.forename: J P
authors.initials: JP
authors.lastname: Revillard
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017637:Clonal Deletion / Q000187:drug effects; D004357:Drug Synergism; D006680:HLA Antigens / Q000235:genetics / Q000494:pharmacology*; D015234:HLA-A Antigens / Q000235:genetics / Q000494:pharmacology; D015235:HLA-B Antigens / Q000235:genetics / Q000494:pharmacology; D015236:HLA-C Antigens / Q000235:genetics / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D015851:Interleukin-7; D015847:Interleukin-4; D007371:Interferon-gamma