RESISTANCE TO APOPTOSIS AND ELEVATED EXPRESSION OF BCL-2 IN CLONALLY EXPANDED CD4(-) T-CELLS FROM RHEUMATOID-ARTHRITIS PATIENTS()CD28()

patients with rheumatoid arthritis have a subset of CD4(+) T lymphocyt es that are characterized by a defect in CD28 expression, CD4(+)CD28(- ) T cells frequently undergo clonal expansion in vivo. These clonotype s include autoreactive cells and persist over many years. The clonogen ic potential and longevity of these T cells could be related to an alt ered response to apoptosis-inducing signals, To explore this possibili ty, CD4(+)CD28(-) T cell lines and clones were examined for their resp onse pattern to stimuli inducing physiologic cell death. CD4(+)CD28(-) T cells were found to be resistant to apoptosis upon withdrawal of th e growth factor, IL-2. To examine whether the altered sensitivity to t his apoptotic signal was correlated with the expression of proteins of the bcl-2 family, the expression of bcl-2, bcl-x, and bar proteins wa s determined. CD28(+) and CD28(-) CD4(+) T cells could not be distingu ished by the levels of bar or bcl-x, protein; however, CD4(+)CD28(-) T cells expressed higher amounts of bcl-2 protein than did CD4(+)CD28() T cells. The increased bcl-2 expression in CD4(+)CD28(-) T cells was relatively independent of signals provided by exogenous IL-2. In CD28 -deficient CD4(+) T cells, bcl-2 was not significantly up-regulated by the addition of exogenous IL-2 and was maintained despite IL-2 withdr awal, as opposed to CD28-expressing CD4(+) T cells, We propose that CD 4(+)CD28(-) T cells are characterized by a dysregulation of the surviv al protein, bcl-2, which may favor the clonal outgrowth of autoreactiv e T cells and thus contribute to the pathogenesis of rheumatoid arthri tis.