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Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
We have shown previously that T cells activated by optimal TCR and
CD28 ligation exhibit marked proliferative heterogeneity, and 
40%
of these activated cells fail entirely to participate in clonal
expansion. To address how prior cell division influences the subsequent
function of primary T cells at the single cell level, primary
CD4+ T cells were subjected to polyclonal stimulation,
sorted based on the number of cell divisions they had undergone, and
restimulated by ligation of TCR/CD28. We find that individual
CD4+ T cells exhibit distinct secondary response patterns
that depend upon their prior division history, such that cells that
undergo more rounds of division show incrementally greater IL-2
production and proliferation in response to restimulation.
CD4+ T cells that fail to divide after activation exist in
a profoundly hyporesponsive state that is refractory to both
TCR/CD28-mediated and IL-2R-mediated proliferative signals. We find
that this anergic state is associated with defects in both TCR-coupled
activation of the p42/44 mitogen-activated protein kinase
(extracellular signal-related kinase 1/2) and IL-2-mediated
down-regulation of the cell cycle inhibitor
p27kip1. However, these defects are selective,
as TCR-mediated intracellular calcium flux and IL-2R-coupled STAT5
activation remain intact in these cells. Therefore, the process of cell
division or cell cycle progression plays an integral role in anergy
avoidance in primary T cells, and may represent a driving force in the
formation of the effector/memory T cell pool.
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