Expansion of CD4+ and CD8+ T cells that have lost the expression of CD28, and are presumably senescent, has been observed in several autoimmune diseases including diabetes mellitus, RA, Wegener's granulomatosis, multiple sclerosis, and ankylosing spondylitis [60–64]. In general, these cells were clonally expanded and included autoreactive T cells, implicating them directly in the pathogenesis of these diseases. In RA, specifically, increased frequencies of CD4+CD28null T cells are associated with more severe disease, again providing evidence for a direct role of these cells in the disease manifestations. In early RA, the frequency of CD4+CD28null T cells is a predictor for erosive progression . In the established disease, the frequency correlates with extra-articular manifestations . Increased frequencies are seen in nodular disease, and the highest frequencies are found in patients with rheumatoid vasculitis. Also, the T-cell type of large granular lymphocytes seen in Felty-like conditions appears to be directly related to the senescent CD28null T cells .
At first sight, the loss of CD28 would suggest that these cells are functionally anergic and prone to apoptosis; however, the opposite is the case. These cells are very potent effector cells, and at least CD4+CD28null T cells are resistant to apoptosis (the data on CD8+ T cells are contradictory) [68–70]. Resistance to apoptosis-inducing signals cannot be attributed to a single mechanism but is acquired and multifactorial, consistent with the senescent phenotype of these cells. CD4+CD28null T cells express more bcl-2, which renders them less sensitive to growth-factor withdrawal . CD4+CD28null T cells are also resistant to Fas-mediated apoptosis. These cells fail to degrade FLIP following T-cell activation and/or IL-2 stimulation. They, therefore, do not activate the death pathway upon Fas-ligand engagement . The resistance to growth-factor withdrawal and Fas signaling may prevent the usual clonal downsizing in vivo after antigen-specific stimulation.
The accumulation of oligoclonal T-cell populations appears to be more the consequence of a prolonged survival than increased proliferation, again consistent with the concept of cellular senescence. Given the central role of T-cell apoptosis in T-cell homeostasis and peripheral tolerance, the prolonged survival of these cells may contribute to their role in inflammatory diseases. Specifically, overexpression of c-FLIP has been shown to induce autoimmunity .
In addition to resistance to apoptosis, other functional and phenotypic changes in senescent T cells in RA are of importance for their role in perpetuating chronic tissue inflammation. First, the shift in regulatory molecules, from the classic CD28-CD80/CD86 pathway to alternate immunoreceptors, changes the cellular context in which T-cell stimulation is facilitated. There is no longer a unique role for professional antigen-presenting cells that express CD80/CD86, but other cell types can be T-cell stimulatory. More importantly, CD4+CD28null T cells are very potent effector T cells and can cause tissue injury by virtue of their high cytotoxic activity and their excessive production of proinflammatory cytokines, including tumor necrosis factor alpha and IFN-γ. There is evidence that both dimensions are of functional importance in RA. Weissman and colleagues  were the first to postulate a role for perforin/granzyme-positive CD4+ T cells in the synovial inflammation of patients with RA, and also in one patient with ankylosing spondylitis. Namekawa and colleagues  demonstrated the presence of these cells in the synovial tissue of patients with RA, again postulating that the gain in cytotoxic function is of functional importance in maintaining chronic synovitis.
Regulatory genes of the KIR family have been identified as disease risk genes in RA and in psoriatic arthritis [73, 74]. In patients with RA, in particular those who have extra-articular manifestations, oligoclonal T-cell populations were found to preferentially express the stimulatory KIR2DS2 gene, often in the absence of inhibitory KIRs or inhibitory receptors of the c-type lectin family, CD94/NKG2A . Indeed, expression of KIR2DS2 had functional implications in that it sensitized the T cells to respond to subthreshold TCR stimulation. The KIR2DS2 gene, present in only 40% of a healthy Caucasian population, was found in association studies to be a risk factor for rheumatoid vasculitis . Association studies also suggested a role for the stimulatory immune receptors, KIR2DS1 and KIR2DS2, in the risk of developing psoriatic arthritis .