Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+) and CD8(+) T cells in vivo.
Programmed death-1 (PD-1) is a recently identified coinhibitory molecule that belongs to the CD28 superfamily. PD-1 has two ligands PD-L1 and PD-L2. There is some evidence that PD-L1 and PD-L2 serve distinct functions, but their exact function in alloimmunity remains unclear. In the present study, we used a GVHD-like model that allows detailed analyses of T-cell activation at a single cell level in vivo to examine the role of PD-1/PD-L1 and PD-1/PD-L2 interactions in regulating proliferation of CD4(+) and CD8(+) T cells in response to alloantigen stimulation. We found that both CD4(+) and CD8(+) T cells proliferated vigorously in vivo and that PD-L1 and PD-L2 exhibit strikingly different effect on T-cell proliferation. While blocking PD-L1 did not affect the in vivo proliferation of CD4(+) and CD8(+) T cells regardless of CD28 costimulation, blocking PD-L2 resulted in a marked increase in the responder frequency of CD8(+) T-cells in vivo. The effect of PD-L2 on the CD8(+) T-cell proliferation is regulated by CD28 costimulation and by the CD4(+) T cells. We conclude that PD-L1 and PD-L2 function differently in regulating alloreactive T-cell activation in vivo, and PD-L2 is predominant in this model in limiting alloreactive CD8(+) T-cell proliferation.
Habicht
A
A
Transplantation Research Center, Brigham and Women's Hospital and the Children's Hospital of Boston, Boston, MA, USA.
Kewalaramani
R
R
Vu
M D
MD
Demirci
G
G
Blazar
B R
BR
Sayegh
M H
MH
Li
X C
XC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D007519:Isoantigens / Q000276:immunology / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D007519:Isoantigens; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein