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

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

Cite this

Prakash, M. D., Munoz, M., Jain, R., Tong, P. L., Koskinen, A. M. L., Regner, M., ... Bird, P. I. (2014). Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. Immunity, 41(6), 960 - 972. https://doi.org/10.1016/j.immuni.2014.11.012
Prakash, Monica D ; Munoz, Marcia ; Jain, Rohit ; Tong, Philip L ; Koskinen, Aulikki M L ; Regner, Matthias ; Kleifeld, Oded ; Ho, Bosco Kwan-Chung ; Olson, Matthew R ; Turner, Stephen J ; Mrass, Paulus ; Weninger, Wolfgang ; Bird, Phillip I. / Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. In: Immunity. 2014 ; Vol. 41, No. 6. pp. 960 - 972.
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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.",
author = "Prakash, {Monica D} and Marcia Munoz and Rohit Jain and Tong, {Philip L} and Koskinen, {Aulikki M L} and Matthias Regner and Oded Kleifeld and Ho, {Bosco Kwan-Chung} and Olson, {Matthew R} and Turner, {Stephen J} and Paulus Mrass and Wolfgang Weninger and Bird, {Phillip I}",
year = "2014",
doi = "10.1016/j.immuni.2014.11.012",
language = "English",
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pages = "960 -- 972",
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Prakash, MD, Munoz, M, Jain, R, Tong, PL, Koskinen, AML, Regner, M, Kleifeld, O, Ho, BK-C, Olson, MR, Turner, SJ, Mrass, P, Weninger, W & Bird, PI 2014, 'Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling', Immunity, vol. 41, no. 6, pp. 960 - 972. https://doi.org/10.1016/j.immuni.2014.11.012

Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. / Prakash, Monica D; Munoz, Marcia; Jain, Rohit; Tong, Philip L; Koskinen, Aulikki M L; Regner, Matthias; Kleifeld, Oded; Ho, Bosco Kwan-Chung; Olson, Matthew R; Turner, Stephen J; Mrass, Paulus; Weninger, Wolfgang; Bird, Phillip I.

In: Immunity, Vol. 41, No. 6, 2014, p. 960 - 972.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling

AU - Prakash, Monica D

AU - Munoz, Marcia

AU - Jain, Rohit

AU - Tong, Philip L

AU - Koskinen, Aulikki M L

AU - Regner, Matthias

AU - Kleifeld, Oded

AU - Ho, Bosco Kwan-Chung

AU - Olson, Matthew R

AU - Turner, Stephen J

AU - Mrass, Paulus

AU - Weninger, Wolfgang

AU - Bird, Phillip I

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AB - 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.

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Prakash MD, Munoz M, Jain R, Tong PL, Koskinen AML, Regner M et al. Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. Immunity. 2014;41(6):960 - 972. https://doi.org/10.1016/j.immuni.2014.11.012