Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling

Monica D Prakash, Marcia Munoz, Rohit Jain, Philip L Tong, Aulikki M L Koskinen, Matthias Regner, Oded Kleifeld, Bosco Kwan-Chung Ho, Matthew R Olson, Stephen J Turner, Paulus Mrass, Wolfgang Weninger, Phillip I Bird

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)960 - 972
Number of pages13
JournalImmunity
Volume41
Issue number6
DOIs
Publication statusPublished - 2014

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