Circulating CD3+CD4+CD28- cells exhibit reduced apoptosis and were found to be more enriched in patients with ankylosing spondylitis than in age-matched healthy control individuals (7.40 ± 6.6% versus 1.03 ± 1.0%; P < 0.001). Levels of CD4+CD28- T cells correlate with disease status as measured using a modified metrology score, but they are independent of age and duration of ankylosing spondylitis. CD4+CD28- T cells produce IFN-γ and perforin, and thus they must be considered proinflammatory and cytotoxic. These T cells share phenotypic and functional properties of natural killer cells, strongly expressing CD57 but lacking the lymphocyte marker CD7. MHC class I recognizing and activating natural killer cell receptors on the surface of CD4+CD28- T cells may be involved in a HLA-B27 mediated co-stimulation of these proinflammatory and cytotoxic cells.