Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.
J Immunol
; 170(2): 711-8, 2003 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-12517932
ABSTRACT
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-2Ralpha 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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Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
/
Receptores de Antígenos de Linfócitos T
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Antígenos de Diferenciação de Linfócitos T
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Citocinas
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Interleucinas
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Interleucina-4
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Interleucina-7
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Antígeno B7-1
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Antígenos CD28
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Interleucina-15
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article