期刊
JOURNAL OF IMMUNOLOGY
卷 175, 期 11, 页码 7372-7379出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.11.7372
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资金
- NCI NIH HHS [CA84500, R01 CA084500] Funding Source: Medline
- NIAID NIH HHS [AI40614, P01 AI056299-03, R01 AI040614, P01 AI039671, R01 AI040614-09, AI056299, AI39671, P01 AI056299, R37 AI038310] Funding Source: Medline
Positive selection during thymocyte development-is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4(+)CD8(+) thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4(+)CD8(+) murine thymocytes. Coligation of TCR and PD-1 on CD4(+)CD8(+) thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4(+)CD8(+) and CD4(+) thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.
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