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* Cambridge Antibody Technology, Abington, United Kingdom;
Wyeth Research, Cambridge, MA 02140
The program death 1 (PD-1) receptor and its ligands, PD-1 ligand
(PD-L)1 and PD-L2, define a novel regulatory pathway with
potential inhibitory effects on T, B, and monocyte responses. In the
present study, we show that human CD4+ T cells express
PD-1, PD-L1, and PD-L2 upon activation, and Abs to the receptor can be
agonists or antagonists of the pathway. Under optimal conditions of
stimulation, ICOS but not CD28 costimulation can be prevented by PD-1
engagement. IL-2 levels induced by costimulation are critical in
determining the outcome of the PD-1 engagement. Thus, low to marginal
IL-2 levels produced upon ICOS costimulation account for the greater
sensitivity of this pathway to PD-1-mediated inhibition. Interestingly,
exogenous IL-2, IL-7, and IL-15 but not IL-4 and IL-21 can rescue PD-1
inhibition, suggesting that among these cytokines only those that
activate STAT5 can rescue PD-1 inhibition. As STAT5 has been implicated
in the maintenance of IL-2R
expression, these results suggest that
IL-7 and IL-15 restore proliferation under conditions of PD-1
engagement by enhancing high-affinity IL-2R expression and hence, IL-2
responsiveness.
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