title: Co-stimulatory pathways controlling activation and peripheral tolerance of human CD4+CD28- T cells.
abstract: Co-stimulation mediated by the CD28 molecule is considered critical in the activation of CD4+ T cells. In patients with rheumatoid arthritis and infrequently in normal individuals, CD4+ T cells lacking CD28 expression are expanded and contain clonogenic populations. To analyze whether these cells are independent of co-stimulatory requirements or whether they use co-stimulatory signals distinct from the CD28 pathway, we have compared CD4+ CD28+ and CD4+ CD28- T cell clones isolated from rheumatoid arthritis patients. Accessory cells supported the induction of CD25 expression as well as of proliferative responses after anti-CD3 cross-linking and prevented the induction of anergy in CD4+ CD28- T cell clones. In contrast to CD4+CD28+ T cells, the presence of accessory cells did not enhance the secretion of interleukin (IL)-2, interferon-gamma, or IL-4. The co-stimulatory signals did not involve CD28/CTLA-4-CD80/CD86 receptor-ligand interactions. The proliferative response of CD4+CD28- T cells could not be blocked by anti-CD2, anti-CD18, and anti-CD58 antibodies, suggesting that these receptor-ligand interactions cannot provide CD28- independent co-stimulation. Our data suggest that CD4+CD28- T cells require co-stimulatory signals for optimal induction of cell growth and CD25 expression as well as for the prevention of anergy. The co-stimulatory receptor-ligand interaction is independent of the CD28 pathway and may be involved in the oligoclonal expansion of the CD4+ CD28- T cell subset in rheumatoid arthritis.
authors.affiliation: Division of Rheumatology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: W
authors.initials: W
authors.lastname: Park
authors.forename: C M
authors.initials: CM
authors.lastname: Weyand
authors.forename: D
authors.initials: D
authors.lastname: Schmidt
authors.forename: J J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002999:Clone Cells; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D015815:Cell Adhesion Molecules; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2