Low-density PD-1 expression on resting human natural killer cells is functional and upregulated after transplantation
Open Access
- 18 February 2021
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 5 (4), 1069-1080
- https://doi.org/10.1182/bloodadvances.2019001110
Abstract
Expression of programmed cell death protein 1 (PD-1) on natural killer (NK) cells has been difficult to analyze on human NK cells. By testing commercial clones and novel anti-PD-1 reagents, we found expression of functional PD-1 on resting human NK cells in healthy individuals and reconstituting NK cells early after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Peripheral blood samples from healthy individuals and transplant recipients were stained for PD-1 expression using the commercial anti-PD-1 clone PD1.3.1.3, fluorescein isothiocyanate (FITC)–labeled pembrolizumab, or an FITC-labeled single-chain variable fragment (scFv) reagent made from pembrolizumab. These reagents identified low yet consistent basal PD-1 expression on resting NK cells, a finding verified by finding lower PD-1 transcripts in sorted NK cells compared with those in resting or activated T cells. An increase in PD-1 expression was identified on paired resting NK cells after allo-HSCT. Blockade of PD-1 on resting NK cells from healthy donors with pembrolizumab did not enhance NK function against programmed death-ligand 1 (PD-L1)–expressing tumor lines, but blocking with its scFv derivative resulted in a twofold increase in NK cell degranulation and up to a fourfold increase in cytokine production. In support of this mechanism, PD-L1 overexpression of K562 targets suppressed NK cell function. Interleukin-15 (IL-15) activity was potent and could not be further enhanced by PD-1 blockade. A similar increase in function was observed with scFv PD-1 blockade on resting blood NK cells after allo-HSCT. We identify the functional importance of the PD-1/PD-L1 axis on human NK cells in which blockade or activation to overcome inhibition will enhance NK cell–mediated antitumor control.This publication has 43 references indexed in Scilit:
- PD-1 is a novel regulator of human B-cell activationInternational Immunology, 2012
- Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9Blood, 2012
- The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibodyBlood, 2010
- In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitorsCancer Immunology, Immunotherapy, 2010
- The PD‐1 pathway in tolerance and autoimmunityImmunological Reviews, 2010
- PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cellsNature Immunology, 2010
- Oncogenic stress sensed by the immune system: role of natural killer cell receptorsNature Reviews Immunology, 2009
- PD‐1 signaling in primary T cellsImmunological Reviews, 2009
- Up on the tightrope: natural killer cell activation and inhibitionNature Immunology, 2008
- In search of the ‘missing self’: MHC molecules and NK cell recognitionImmunology Today, 1990