Serine Protease Inhibitor 6 Protects Cytotoxic T Cells from Self-Inflicted Injury by Ensuring the Integrity of Cytotoxic Granules

Manling Zhang; Sun Mi Park; Yue Wang; Ramila Shah; Ni Liu; Andrea E. Murmann; Chyung Ru Wang; Marcus E. Peter; Philip G. Ashton-Rickardt

doi:10.1016/j.immuni.2006.02.002

Serine Protease Inhibitor 6 Protects Cytotoxic T Cells from Self-Inflicted Injury by Ensuring the Integrity of Cytotoxic Granules

Manling Zhang, Sun Mi Park, Yue Wang, Ramila Shah, Ni Liu, Andrea E. Murmann, Chyung Ru Wang, Marcus E. Peter, Philip G. Ashton-Rickardt^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

109 Scopus citations

Abstract

How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.

Original language	English (US)
Pages (from-to)	451-461
Number of pages	11
Journal	Immunity
Volume	24
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2006.02.002
State	Published - Apr 2006

Funding

We would like to thank R. Welsh for high titer stocks of LCMV Armstrong and Y. Chen of the University of Chicago Electron Microscopy Core facility for TEM. We thank G. Franzoso and S. Byrne for useful comments on the paper and F. Tang for help with Western blots. Supported by NIH grant AI45108 to P.G.A.-R.

Keywords

CELLIMMUNO
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2006.02.002

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title = "Serine Protease Inhibitor 6 Protects Cytotoxic T Cells from Self-Inflicted Injury by Ensuring the Integrity of Cytotoxic Granules",

abstract = "How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.",

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author = "Manling Zhang and Park, {Sun Mi} and Yue Wang and Ramila Shah and Ni Liu and Murmann, {Andrea E.} and Wang, {Chyung Ru} and Peter, {Marcus E.} and Ashton-Rickardt, {Philip G.}",

note = "Funding Information: We would like to thank R. Welsh for high titer stocks of LCMV Armstrong and Y. Chen of the University of Chicago Electron Microscopy Core facility for TEM. We thank G. Franzoso and S. Byrne for useful comments on the paper and F. Tang for help with Western blots. Supported by NIH grant AI45108 to P.G.A.-R. ",

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doi = "10.1016/j.immuni.2006.02.002",

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AU - Zhang, Manling

AU - Park, Sun Mi

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AU - Shah, Ramila

AU - Liu, Ni

AU - Murmann, Andrea E.

AU - Wang, Chyung Ru

AU - Peter, Marcus E.

AU - Ashton-Rickardt, Philip G.

N1 - Funding Information: We would like to thank R. Welsh for high titer stocks of LCMV Armstrong and Y. Chen of the University of Chicago Electron Microscopy Core facility for TEM. We thank G. Franzoso and S. Byrne for useful comments on the paper and F. Tang for help with Western blots. Supported by NIH grant AI45108 to P.G.A.-R.

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N2 - How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.

AB - How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.

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Serine Protease Inhibitor 6 Protects Cytotoxic T Cells from Self-Inflicted Injury by Ensuring the Integrity of Cytotoxic Granules

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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