Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells

• Published in: Blood 2007-07, Vol.110 (1), p.186-192
• Main Authors: Goldberg, Monica V., Maris, Charles H., Hipkiss, Edward L., Flies, Andrew S., Zhen, Lijie, Tuder, Rubin M., Grosso, Joseph F., Harris, Timothy J., Getnet, Derese, Whartenby, Katharine A., Brockstedt, Dirk G., Dubensky, Thomas W., Chen, Lieping, Pardoll, Drew M., Drake, Charles G.
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Antigen specific factors; Antigens, Surface - physiology; Apoptosis Regulatory Proteins - physiology; Autoantigens; B7-1 Antigen - physiology; B7-H1 Antigen; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Membrane Glycoproteins - physiology; Mice; Peptides - physiology; Programmed Cell Death 1 Ligand 2 Protein; Programmed Cell Death 1 Receptor; Protein Binding; Regulatory factors and their cellular receptors; Self Tolerance; T-Lymphocytes, Cytotoxic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-12-062422

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. Furthermore, PD-1 up-regulation 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. In this study, we evaluate the role of PD-1 and its 2 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 cytolytic T lymphocytes (CTLs). These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell–fate decisions.