Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.
Pathways in the B7:CD28 family of costimulatory molecules regulate T cell activation and tolerance. B7-dependent responses in Cd28(-/-)Ctla4(-/-) T cells together with reports of stimulatory and inhibitory functions for Programmed Death-1 Ligand 1 or 2 molecules (PD-L1 or PD-L2) have suggested additional receptors for these B7 family members. We show that B7-1 and PD-L1 interacted with affinity intermediate to that of B7-1:CD28 and B7-1:CTLA-4. The PD-L1:B7-1 interface overlapped with the B7-1:CTLA-4 and PD-L1:PD-1 (Programmed Death-1) interfaces. T cell activation and cytokine production were inhibited by the interaction of B7-1 with PD-L1. The responses of PD-1-deficient versus PD-1,B7-1 double-deficient T cells to PD-L1 and of CD28,CTLA-4 double-deficient versus CD28,CTLA-4,PD-L1 triple-deficient T cells to B7-1 demonstrated that PD-L1 and B7-1 interact specifically to inhibit T cell activation. Our findings point to a substantial bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family.
Butte
Manish J
MJ
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Keir
Mary E
ME
Phamduy
Theresa B
TB
Sharpe
Arlene H
AH
Freeman
Gordon J
GJ
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D060890:B7-H1 Antigen; D019556:COS Cells; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides