TY - JOUR
T1 - Frontline science
T2 - Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1
AU - Patera, Andriani C.
AU - Drewry, Anne M.
AU - Chang, Katherine
AU - Beiter, Evan R.
AU - Osborne, Dale
AU - Hotchkiss, Richard S.
N1 - Funding Information:
This work was supported by U.S. National Institutes of Health (NIH) Grant GM 44118 and by a research grant to R.S.H. from MedImmune LLC. A.M.D. was supported by Grant KL2TR000450 from the National Center for Advancing Translational Sciences of the NIH. We thank Dr. Taylor Cohen, MedImmune, LLC, for critical review of the manuscript.
Publisher Copyright:
© Society for Leukocyte Biology.
PY - 2016/12
Y1 - 2016/12
N2 - Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1+ -suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1+LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8+ T cells and NK cells. Conversely, reduced CD8+ T cell and NK cell functions (IFN-g production, granzyme B, and CD107a expression) correlated with elevated PD-L1+ LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsisimmune suppression and the ability to treat multiple deficits with a single immunomodulatory agent.
AB - Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1+ -suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1+LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8+ T cells and NK cells. Conversely, reduced CD8+ T cell and NK cell functions (IFN-g production, granzyme B, and CD107a expression) correlated with elevated PD-L1+ LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsisimmune suppression and the ability to treat multiple deficits with a single immunomodulatory agent.
KW - Immunosuppression
KW - Monocytes
KW - Neutrophils
KW - Programmed cell death
UR - http://www.scopus.com/inward/record.url?scp=85002824021&partnerID=8YFLogxK
U2 - 10.1189/jlb.4HI0616-255R
DO - 10.1189/jlb.4HI0616-255R
M3 - Article
C2 - 27671246
AN - SCOPUS:85002824021
SN - 0741-5400
VL - 100
SP - 1239
EP - 1254
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 6
ER -