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Departments of Medicine and Immunology, Mayo Clinic and Foundation, Rochester, MN 55905
CD4+CD28null T cells are oligoclonal
lymphocytes rarely found in healthy individuals younger than 40 yr, but
are found in high frequencies in elderly individuals and in patients
with chronic inflammatory diseases. Contrary to paradigm, they are
functionally active and persist over many years. Such clonogenic
potential and longevity suggest altered responses to apoptosis-inducing
signals. In this study, we show that
CD4+CD28null T cells are protected from
undergoing activation-induced cell death. Whereas CD28+ T
cells underwent Fas-mediated apoptosis upon cross-linking of CD3,
CD28null T cells were highly resistant.
CD28null T cells were found to progress through the cell
cycle, and cells at all stages of the cell cycle were resistant to
apoptosis, unlike their CD28+ counterparts. Neither the
activation-induced up-regulation of the IL-2R 
-chain (CD25) nor the
addition of exogenous IL-2 renders them susceptible to Fas-mediated
apoptosis. These properties of CD28null T cells were
related to high levels of Fas-associated death domain-like
IL-1-converting enzyme-like inhibitory protein, an 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 CD28null cells from spontaneous cell death, the present
studies unequivocally show dysregulation of apoptotic pathways in
CD4+CD28null T cells that favor their clonal
outgrowth and maintenance in vivo.
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