OBJECTIVE: It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA). METHODS: Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [(3)H]thymidine incorporation and CD8(high) cytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies. RESULTS: CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8(high)CD101- T cells exhibited greater cytotoxic activity than CD8(high)CD101+ T cells, while no difference was observed between CD4CD25(high)CD101+ and CD4CD25(high)CD101- Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab')(2) fragment. CONCLUSION: These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8(high)CD101+ T cells were markedly less cytotoxic than CD8(high) T cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.