title: Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling.
abstract: Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Monica D
authors.initials: MD
authors.lastname: Prakash
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Munoz
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Rohit
authors.initials: R
authors.lastname: Jain
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Tong
authors.affiliation: Department of Emerging Pathogens and Vaccines, John Curtin School of Medical Research, College of Medicine, Biology, and Environment, Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Aulikki
authors.initials: A
authors.lastname: Koskinen
authors.affiliation: Department of Emerging Pathogens and Vaccines, John Curtin School of Medical Research, College of Medicine, Biology, and Environment, Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Regner
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Oded
authors.initials: O
authors.lastname: Kleifeld
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Bosco
authors.initials: B
authors.lastname: Ho
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Olson
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia.
authors.forename: Paulus
authors.initials: P
authors.lastname: Mrass
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, NSW 2006, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia. Electronic address: phil.bird@monash.edu.
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004481:Ectromelia virus / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000502:physiology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology* / Q000821:virology; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics
chemical_list: D018925:Chemokines; D016326:Extracellular Matrix Proteins; D053804:Granzymes