Clonality and longevity of CD4(+)CD28(null) T cells are associated with defects in apoptotic pathways

CD4(+)CD28(null) T cells are oligoclonal lymphocytes rarely found in health y individuals younger than 40 yr, but are found in high frequencies in elde rly individuals and in patients with chronic inflammatory diseases. Contrar y to paradigm, they are functionally; active and persist over many years. S uch clonogenic potential and longevity suggest altered responses to apoptos is-inducing signals. In this study, we show that CD4(+)CD28(null) T cells a re protected from undergoing activation-induced cell death. Whereas CD28(+) T cells underwent Fas-mediated apoptosis upon cross-linking of CD3, CD28(n ull) T cells were highly resistant, CD28(null) T cells were found to progre ss through the cell cycle, and cells at all stages of the cell cycle were r esistant to apoptosis, unlike their CD28(+) counterparts. Neither the activ ation-induced up-regulation of the IL-2R alpha -chain (CD25) nor the additi on of exogenous IL-2 renders them susceptible to Fas-mediated apoptosis, Th ese properties of CD28(null) T cells were related to high levels of Fas-ass ociated death domain-like IL-1-converting enzyme-like inhibitory protein, a n inhibitor of Fas signaling that is normally degraded in T cells following activation in the presence of IL-2, Consistent with previous data showing protection of CD28(null) cells from spontaneous cell death, the present stu dies unequivocally show dysregulation of apoptotic pathways in CD4(+)CD28(n ull) T cells that favor their clonal outgrowth and maintenance in vivo.