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Blood, 1 July 2007, Vol. 110, No. 1, pp. 186-192.
Prepublished online as a Blood First Edition Paper on March 28, 2007; DOI 10.1182/blood-2006-12-062422.
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Submitted December 12, 2006
Accepted March 20, 2007
Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells
Monica V Goldberg, Charles H Maris, Edward L Hipkiss, Andrew S Flies, Lijie Zhen, Rubin M Tuder, Joseph F Grosso, Timothy J Harris, Derese Getnet, Katharine A Whartenby, Dirk G Brockstedt, Thomas W Dubensky Jr, Lieping Chen, Drew M Pardoll, and Charles G Drake*
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States
Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
Cerus Corporation, Concord, CA, United States
* Corresponding author; email: drakech{at}jhmi.edu.
Expression of the PD-1 receptor on T cells has been shown to provide an important inhibitory signal that down-modulates peripheral effector responses in normal tissues and tumors. Further, PD-1 upregulation on chronically activated T cells can maintain them in a partially reversible inactive state. The function of PD-1 in the very early stages of T cell response to antigen in vivo has not been fully explored. Here we evaluate the role of PD-1 and its two B7 family ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), in early fate decisions of CD8 T cells. We show that CD8 T cells specific for influenza hemagglutinin (HA) expressed as a self-antigen become functionally tolerized and express high levels of surface PD-1 by the time of their first cell division. Blockade of PD-1 or B7-H1, but not B7-DC, at the time of self-antigen encounter mitigates tolerance induction and results in CD8 T cell differentiation into functional CTL. These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T cell fate decisions.
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