{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T02:09:09Z","timestamp":1779242949586,"version":"3.51.4"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T00:00:00Z","timestamp":1277942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The role played by apoptosis in the homeostasis of effector cells of the innate immune system is unclear. Serine protease inhibitor 6 (Spi6) is an inhibitor of granzyme B (GrB) that protects cytotoxic T lymphocytes of the adaptive immune system from apoptosis. To determine whether Spi6 also protects cells of the innate immune system from self-inflicted damage we have examined invariant NKT (iNKT) cells. Spi6-deficient iNKT cells harbored increased levels of GrB after TCR stimulation with the PBS-57 glycolipid Ag and were susceptible to apoptosis. The increased apoptosis of Spi6 knock-out (KO) iNKT cells lead to a complete loss in the production of IL-4 and IFN-\u03b3 by Spi6 KO iNKT cells after PBS-57 challenge. The increased activation-induced apoptosis resulted in impaired survival and a decreased clonal burst size of Spi6 KO iNKT cells, which could be corrected by GrB deficiency. However, the clonal burst of Spi6 KO iNKT cells after TCR-independent activation with lymphocytic choriomeningitis virus was not affected. Our findings demonstrate that Spi6 protects cytotoxic cells of the innate immune system from GrB-mediated self-inflicted triggered by the recognition of Ag.<\/jats:p>","DOI":"10.4049\/jimmunol.1000651","type":"journal-article","created":{"date-parts":[[2010,6,12]],"date-time":"2010-06-12T02:17:23Z","timestamp":1276309043000},"page":"877-883","source":"Crossref","is-referenced-by-count":24,"title":["Serine Protease Inhibitor 6 Protects iNKT Cells from Self-Inflicted Damage"],"prefix":"10.1093","volume":"185","author":[{"given":"A Wahid","family":"Ansari","sequence":"first","affiliation":[{"name":"Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff N","family":"Temblay","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syarifah H","family":"Alyahya","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip G","family":"Ashton-Rickardt","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London , London ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,7,15]]},"reference":[{"key":"2025032411412065000_r1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nri1309","article-title":"NKT cells: what\u2019s in a name?","volume":"4","author":"Godfrey","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411412065000_r2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","article-title":"The biology of NKT cells","volume":"25","author":"Bendelac","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411412065000_r3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nature05907","article-title":"CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor","volume":"448","author":"Borg","year":"2007","journal-title":"Nature"},{"key":"2025032411412065000_r4","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1146\/annurev.immunol.22.012703.104608","article-title":"CD1: antigen presentation and T cell function","volume":"22","author":"Brigl","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411412065000_r5","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1146\/annurev.immunol.23.021704.115742","article-title":"Toward an understanding of NKT cell biology: progress and paradoxes","volume":"23","author":"Kronenberg","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411412065000_r6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1615\/CritRevImmunol.v25.i3.20","article-title":"iNKT-cell responses to glycolipids","volume":"25","author":"Parekh","year":"2005","journal-title":"Crit. Rev. Immunol."},{"key":"2025032411412065000_r7","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1146\/annurev.immunol.21.120601.141057","article-title":"The regulatory role of Valpha14 NKT cells in innate and acquired immune response","volume":"21","author":"Taniguchi","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411412065000_r8","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2174\/0929867043456115","article-title":"Alpha-galactosylceramide: potential immunomodulatory activity and future application","volume":"11","author":"Hayakawa","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"2025032411412065000_r9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jim.2006.02.009","article-title":"A modified alpha-galactosyl ceramide for staining and stimulating natural killer T cells","volume":"312","author":"Liu","year":"2006","journal-title":"J. Immunol. Methods"},{"key":"2025032411412065000_r10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S1074-7613(00)80617-2","article-title":"Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis","volume":"9","author":"Eberl","year":"1998","journal-title":"Immunity"},{"key":"2025032411412065000_r11","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.4049\/jimmunol.171.8.4020","article-title":"Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells","volume":"171","author":"Crowe","year":"2003","journal-title":"J. Immunol."},{"key":"2025032411412065000_r12","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/intimm\/dxh023","article-title":"Down-regulation of the invariant Valpha14 antigen receptor in NKT cells upon activation","volume":"16","author":"Harada","year":"2004","journal-title":"Int. Immunol."},{"key":"2025032411412065000_r13","doi-asserted-by":"crossref","first-page":"10913","DOI":"10.1073\/pnas.1833166100","article-title":"The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion","volume":"100","author":"Wilson","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411412065000_r14","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.4049\/jimmunol.175.5.3092","article-title":"NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge","volume":"175","author":"Uldrich","year":"2005","journal-title":"J. Immunol."},{"key":"2025032411412065000_r15","doi-asserted-by":"crossref","first-page":"4367","DOI":"10.4049\/jimmunol.165.8.4367","article-title":"Fas\/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes","volume":"165","author":"Leite-de-Moraes","year":"2000","journal-title":"J. Immunol."},{"key":"2025032411412065000_r16","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev.immunol.20.100201.131730","article-title":"Lymphocyte-mediated cytotoxicity","volume":"20","author":"Russell","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411412065000_r17","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/369031a0","article-title":"Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice","volume":"369","author":"K\u00e4gi","year":"1994","journal-title":"Nature"},{"key":"2025032411412065000_r18","doi-asserted-by":"crossref","first-page":"8629","DOI":"10.1073\/pnas.82.24.8629","article-title":"Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules","volume":"82","author":"Podack","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411412065000_r19","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/0092-8674(94)90376-X","article-title":"Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells","volume":"76","author":"Heusel","year":"1994","journal-title":"Cell"},{"key":"2025032411412065000_r20","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1615\/CritRevImmunol.v25.i3.10","article-title":"The granule pathway of programmed cell death","volume":"25","author":"Ashton-Rickardt","year":"2005","journal-title":"Crit. Rev. Immunol."},{"key":"2025032411412065000_r21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0014-5793(93)81143-N","article-title":"The ovalbumin family of serpin proteins","volume":"315","author":"Remold-O\u2019Donnell","year":"1993","journal-title":"FEBS Lett."},{"key":"2025032411412065000_r22","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.4049\/jimmunol.173.6.3801","article-title":"A role for the granzyme B inhibitor serine protease inhibitor 6 in CD8+ memory cell homeostasis","volume":"173","author":"Phillips","year":"2004","journal-title":"J. Immunol."},{"key":"2025032411412065000_r23","doi-asserted-by":"crossref","first-page":"15434","DOI":"10.1074\/jbc.272.24.15434","article-title":"A new family of 10 murine ovalbumin serpins includes two homologs of proteinase inhibitor 8 and two homologs of the granzyme B inhibitor (proteinase inhibitor 9)","volume":"272","author":"Sun","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2025032411412065000_r24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.immuni.2006.02.002","article-title":"Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules","volume":"24","author":"Zhang","year":"2006","journal-title":"Immunity"},{"key":"2025032411412065000_r25","doi-asserted-by":"crossref","first-page":"3483","DOI":"10.4049\/jimmunol.178.6.3483","article-title":"Differential survival of cytotoxic T cells and memory cell precursors","volume":"178","author":"Zhang","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411412065000_r26","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.4049\/jimmunol.178.5.2827","article-title":"IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production","volume":"178","author":"Coquet","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411412065000_r27","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1002\/eji.200939800","article-title":"NKT cells: friend or foe during viral infections?","volume":"39","author":"Diana","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025032411412065000_r28","doi-asserted-by":"crossref","first-page":"10746","DOI":"10.1128\/JVI.75.22.10746-10754.2001","article-title":"Selective loss of natural killer T cells by apoptosis following infection with lymphocytic choriomeningitis virus","volume":"75","author":"Hobbs","year":"2001","journal-title":"J. Virol."},{"key":"2025032411412065000_r29","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/eji.200425495","article-title":"Long-term loss of canonical NKT cells following an acute virus infection","volume":"35","author":"Lin","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025032411412065000_r30","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.4049\/jimmunol.172.6.3454","article-title":"CD1d1-dependent control of the magnitude of an acute antiviral immune response","volume":"172","author":"Roberts","year":"2004","journal-title":"J. Immunol."},{"key":"2025032411412065000_r31","doi-asserted-by":"crossref","first-page":"27802","DOI":"10.1074\/jbc.271.44.27802","article-title":"A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes","volume":"271","author":"Sun","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2025032411412065000_r32","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1002\/eji.200324376","article-title":"Granzyme B leakage-induced cell death: a new type of activation-induced natural killer cell death","volume":"33","author":"Ida","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"2025032411412065000_r33","doi-asserted-by":"crossref","first-page":"32339","DOI":"10.1074\/jbc.M205153200","article-title":"Selective inhibition of dipeptidyl peptidase I, not caspases, prevents the partial processing of procaspase-3 in CD3-activated human CD8(+) T lymphocytes","volume":"277","author":"Bid\u00e8re","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2025032411412065000_r34","doi-asserted-by":"crossref","first-page":"4452","DOI":"10.4049\/jimmunol.181.7.4452","article-title":"Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals","volume":"181","author":"Tyznik","year":"2008","journal-title":"J. Immunol."},{"key":"2025032411412065000_r35","doi-asserted-by":"crossref","first-page":"19461","DOI":"10.1073\/pnas.0908249106","article-title":"Transcriptional regulator Id2 controls survival of hepatic NKT cells","volume":"106","author":"Monticelli","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411412065000_r36","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/ni1403","article-title":"Transcriptional regulator Id2 mediates CD8+ T cell immunity","volume":"7","author":"Cannarile","year":"2006","journal-title":"Nat. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/2\/877\/62467559\/1000651.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/2\/877\/62467559\/1000651.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T22:00:21Z","timestamp":1743199221000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/185\/2\/877\/7977450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,7]]},"references-count":36,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2010,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1000651","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,7]]},"published":{"date-parts":[[2010,7]]}}}