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‐γ, 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.