International Immunology, Vol 10, 969-979, Copyright © 1998 by Oxford University Press
A Grakoui, LF VanDyk, SF Dowdy and PM Allen
In this report, we explore the mechanisms underlying cell cycle progression
in T cells stimulated with an altered peptide ligand (APL) versus wild-type
peptide. APL stimulation did not induce proliferation compared to wild-type
peptide stimulation. To determine the point at which cell cycle progression
is blocked, we have examined molecules responsible for regulating the
retinoblastoma tumor suppressor gene product, pRb, which in its active
state prevents G1/S progression. The majority of cells stimulated with an
APL did not progress beyond G1; however, a small population did make the
G1/S transition. These few cells passed the late G1 restriction point,
divided and subsequently arrested at the next G1 phase. The lack of
sustained signaling events following stimulation with an APL failed to
induce cyclin E:cdk2 activity, a regulator which hyper-phosphorylates and
inactivates pRb. Exogenous IL-2 addition did not compensate for the lack of
proliferation following APL stimulation. Furthermore, the inability of the
cells to enter S phase during partial T cell activation cannot be accounted
for by p27Kip1 inhibition of cyclin E:cdk2 complexes. Upon APL stimulation,
an increase in association of p27Kip1 with cyclin E:cdk2 complex was not
observed, suggesting that instead, decreased cyclin E:cdk complex formation
might contribute to the failure to progress from G1/S. Therefore, while for
a majority of cells, wild-type stimulation results in cell cycle
progression, APL stimulation is not sufficient to drive cells beyond G1.
ARTICLES
Molecular basis for the lack of T cell proliferation induced by an altered peptide ligand
Center for Immunology and Department of Pathology, Washington University School of Medicine, St Louis, MO 63110, USA.
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