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.
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.
Bennett
Frann
F
Cambridge Antibody Technology, Abington, United Kingdom.
Luxenberg
Deborah
D
Ling
Vincent
V
Wang
I-Ming
IM
Marquette
Kim
K
Lowe
David
D
Khan
Nighat
N
Veldman
Geertruida
G
Jacobs
Kenneth A
KA
Valge-Archer
Viia E
VE
Collins
Mary
M
Carreno
Beatriz M
BM
D000906:Antibodies / Q000502:physiology; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis* / Q000502:physiology; D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000096:biosynthesis / Q000502:physiology; D018106:CD28 Antigens / Q000096:biosynthesis*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D036341:Intercellular Signaling Peptides and Proteins; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis*; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000502:physiology; D007378:Interleukins / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins; D010455:Peptides / Q000502:physiology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D020395:Receptors, Interleukin-7 / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; D018106:CD28 Antigens; D016207:Cytokines; C556692:ICOS protein, human; C507941:IL2RG protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D036341:Intercellular Signaling Peptides and Proteins; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D015847:Interleukin-4; D000098546:Interleukin-21