Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway.
Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1(+) T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8(+) T cells, but not of CD4(+) T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1(+) T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1(-) T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1(-) T cells may prove to be a helpful strategy in enhancing primary responses.
Lages
Celine S
CS
Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, OH 45229, USA.
Lewkowich
Ian
I
Sproles
Alyssa
A
Wills-Karp
Marsha
M
Chougnet
Claire
C
D000375:Aging; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D005434:Flow Cytometry; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000378:metabolism*
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor