Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1.
Bacteria colonize cystic fibrosis (CF) airways, and although T cells with appropriate Ag specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited massively into the CF airway lumen and actively exocytosing primary granules, also suppress T cell function therein. Programmed death-ligand 1 (PD-L1), which exerts T cell suppression at a late step, was expressed bimodally on CF airway PMNs, delineating PD-L1(hi) and PD-L1(lo) subsets, whereas healthy control (HC) airway PMNs were uniformly PD-L1(hi). Blood PMNs incubated in CF airway fluid lost PD-L1 over time; in coculture, Ab blockade of PD-L1 failed to inhibit the suppression of T cell proliferation by CF airway PMNs. In contrast with PD-L1, arginase 1 (Arg1), which exerts T cell suppression at an early step, was uniformly high on CF and HC airway PMNs. However, arginase activity was high in CF airway fluid and minimal in HC airway fluid, consistent with the fact that Arg1 activation requires primary granule exocytosis, which occurs in CF, but not HC, airway PMNs. In addition, Arg1 expression on CF airway PMNs correlated negatively with lung function and positively with arginase activity in CF airway fluid. Finally, combined treatment with arginase inhibitor and arginine rescued the suppression of T cell proliferation by CF airway fluid. Thus, Arg1 and PD-L1 are dynamically modulated upon PMN migration into human airways, and, Arg1, but not PD-L1, contributes to early PMN-driven T cell suppression in CF, likely hampering resolution of infection and inflammation.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322;
Sarah A
SA
Ingersoll
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322;
Julie
J
Laval
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322;
Osric A
OA
Forrest
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322;
Marcela
M
Preininger
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322;
Milton R
MR
Brown
Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, GA 30313; and.
Dalia
D
Arafat
Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, GA 30313; and.
Greg
G
Gibson
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Vin
V
Tangpricha
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; Center for Cystic Fibrosis and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322; tirouvanziam@emory.edu.
Rabindra
R
Tirouvanziam
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D001119:Arginase / Q000096:biosynthesis / Q000276:immunology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D049109:Cell Proliferation; D003550:Cystic Fibrosis / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C574619:ARG1 protein, human; D001119:Arginase