PDGF-D-PDGFRβ signaling enhances IL-15-mediated human natural killer cell survival

Shoubao Ma; Tingting Tang; Xiaojin Wu; Anthony G Mansour; Ting Lu; Jianying Zhang; Li-Shu Wang; Michael A Caligiuri; Jianhua Yu

doi:10.1073/pnas.2114134119

PDGF-D-PDGFRβ signaling enhances IL-15-mediated human natural killer cell survival

Proc Natl Acad Sci U S A. 2022 Jan 18;119(3):e2114134119. doi: 10.1073/pnas.2114134119.

Authors

Shoubao Ma^{1

2}, Tingting Tang¹, Xiaojin Wu³, Anthony G Mansour¹, Ting Lu¹, Jianying Zhang⁴, Li-Shu Wang⁵, Michael A Caligiuri^{6

2

7}, Jianhua Yu^{6

2

7}

Affiliations

¹ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010.
² Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010.
³ Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215123, China.
⁴ Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010.
⁵ Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226.
⁶ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010; [email protected] [email protected].
⁷ Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010.

Abstract

The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRβ) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)-induced human NK cell survival but not effector functions via its binding to PDGFRβ but independent of its binding to NKp44. Resting NK cells express no PDGFRβ and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15-induced expression of PDGFRβ improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D-PDGFRβ signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions.

Keywords: IL-15; NK cells; PDGF-D; PDGFRβ; cell survival.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Proliferation / drug effects
Cell Survival / drug effects
Humans
Interleukin-15 / metabolism*
Killer Cells, Natural / metabolism*
Lymphokines
Mice
Mice, Inbred C57BL
NF-kappa B / metabolism
Natural Cytotoxicity Triggering Receptor 2
Platelet-Derived Growth Factor / metabolism*
Platelet-Derived Growth Factor / pharmacology
Receptor, Platelet-Derived Growth Factor beta / genetics
Receptor, Platelet-Derived Growth Factor beta / metabolism*
Signal Transduction / physiology*

Substances

IL15 protein, human
Interleukin-15
Lymphokines
NCR2 protein, human
NF-kappa B
Natural Cytotoxicity Triggering Receptor 2
PDGFD protein, human
Platelet-Derived Growth Factor
Receptor, Platelet-Derived Growth Factor beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding