Single cell profiling of hematopoietic stem cell transplant recipients reveals TGF-β1 and IL-2 confer immunoregulatory functions to NK cells
Jessica A. Mathews,
Dorota T. Borovsky,
Kyle T. Reid,
Julia M. Murphy,
Sarah J. Colpitts,
Abel Santos Carreira,
Tommy Alfaro Moya,
Douglas C. Chung,
Igor Novitzky-Basso,
Jonas Mattsson,
Pamela S. Ohashi,
Sarah Q. Crome
Affiliations
Jessica A. Mathews
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Dorota T. Borovsky
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Kyle T. Reid
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Julia M. Murphy
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Sarah J. Colpitts
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Abel Santos Carreira
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Tommy Alfaro Moya
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Douglas C. Chung
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Igor Novitzky-Basso
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Jonas Mattsson
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Pamela S. Ohashi
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2C4, Canada
Sarah Q. Crome
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: Natural killer (NK) cell activity is influenced by cytokines and microenvironment factors, resulting in remarkably diverse functions, by contributing to inflammatory responses or serving as rheostats of adaptive immunity. Using single cell RNA sequencing (scRNA-seq), we identified a TGFβ1highCD56brightNK cell population associated with hematopoietic stem cell transplant recipients protected from acute graft-versus-host disease (GVHD). We further define a role for the combination of interleukin-2 (IL-2) and transforming growth factor β1 (TGF-β1) in promoting a regulatory phenotype in NK cells. “Induced” regulatory NK cells produce high amounts of TGF-β1, inhibited T cells, could promote naive T cells differentiation into regulatory T cells, and exhibited a unique transcriptional program that includes expression of IKZF2 (HELIOS) and ZNF683 (HOBIT). This phenotype was not stable, and “induced” regulatory NK cells lost the ability to secrete TGF-β1 upon exposure to different cytokines. These findings define protective CD56brightNK cells post-hematopoietic stem cell transplantation, and demonstrate the combination of IL-2 and TGF-β1 promotes regulatory activity in NK cells.
