title: Functionally anergic lpr and gld B220+ T cell receptor (TCR)-alpha/beta+ double-negative T cells express CD28 and respond to costimulation with phorbol myristate acetate and antibodies to CD28 and the TCR.
abstract: Mice homozygous for lpr and gld develop lymphadenopathy characterized by the progressive accumulation of an unusual population of CD4-, CD8-, CD2-, IL-2R- double-negative (DN) T cells that express reduced levels of TCR-alpha/beta, high levels of CD45 (B220) and Ly-6C and variable levels of CD69. These cells are refractory to most stimuli, including staphylococcal entertoxins and cross-linking of the TCR, Ly-6C, and CD69. For normal T cells, the binding of ligand to the TCR alone is insufficient to induce a proliferative response and can result in the induction of a state of prolonged anergy. Efficient stimulation is dependent on the delivery of a second or costimulatory signal. Recently it was reported that CD28 can provide costimulatory signals to T cells and, that these signals can prevent anergy induction in T cell clones. We investigated the possibility that lpr and gld DN T cells are unresponsive because they fail to transduce signals via CD28. These studies showed that highly purified B220+ TCR-alpha/beta+ DN T cells expressed high levels of CD28, responded weakly to stimulation with PMA and anti-CD28 mAb and quite strongly to PMA, anti-CD28 antibody and high concentrations of immobilized anti-TCR-alpha/beta antibodies. The latter stimulus also induced low levels of expression of CD2 and IL-2R and secretion of modest amounts of IL-2. Although DN T cells proliferated and secreted IL-2, these responses differed qualitatively and quantitatively from those of +/+ and lprB220- T cells. Consistent with its effects on normal T cells, cyclosporin A partially inhibited the response of DN T cells to TCR cross-linking and CD28 ligation. Studies of synergism between CD28-, Ly-6C-, and CD69-mediated signals revealed that ligation of CD28 enhanced the proliferative response induced by cross-linking of Ly-6C or CD69 on +/+, lpr and gld B220- T cells but had no effect on the unresponsiveness of DN T cells to these stimuli. Ligation of CD28 did not reverse the unresponsiveness of DN T cells to SEB and had only a weak synergistic effect on the response of B220- T cells. Together, these observations suggest that the mechanisms leading to immunosuppression of DN T cells are complex and appear to involve abnormalities in signal transduction via the TCR and CD28 and possibly via Ly-6C and CD69 as well.
authors.affiliation: Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: T
authors.initials: T
authors.lastname: Giese
authors.forename: J P
authors.initials: JP
authors.lastname: Allison
authors.forename: W F
authors.initials: WF
authors.lastname: Davidson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis* / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis* / Q000502:physiology; D000954:Antigens, Surface / Q000032:analysis*; D001327:Autoimmune Diseases / Q000276:immunology*; D018106:CD28 Antigens; D015704:CD4 Antigens / Q000032:analysis*; D016827:CD8 Antigens / Q000032:analysis*; D016572:Cyclosporine / Q000494:pharmacology; D004768:Enterotoxins / Q000276:immunology; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000378:metabolism; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D018106:CD28 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D004768:Enterotoxins; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; C031818:enterotoxin B, staphylococcal; D016572:Cyclosporine; D017493:Leukocyte Common Antigens; D013755:Tetradecanoylphorbol Acetate