{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T05:28:24Z","timestamp":1771997304963,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,11,17]],"date-time":"2005-11-17T00:00:00Z","timestamp":1132185600000},"content-version":"vor","delay-in-days":3883,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[1995,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>CD8<jats:sup>+<\/jats:sup> cytotoxic T lymphocyte (CTL) clones begin to synthesize the lytic proteins granzyme A, granzyme B and perforin after stimulation with allogeneic target cells. The lytic proteins are stored in the secretory granules which are released after cross\u2010linking of the T cell receptor (TcR) upon target cell recognition. During lytic granule biogenesis granzyme A protein synthesis can be detected between 2 and 10 days after allogeneic stimulation of the CTL. Although granzyme A is stored in the lytic granules over this period, the majority of granzyme A synthesized is secreted directly from the CTL.<\/jats:p><jats:p>TcR triggering of degranulation also results in new synthesis of the lytic proteins, which can be inhibited by cycloheximide (CHX). Some of the newly synthesized lytic proteins can be stored in the cell and refill the granules. But up to one third of granzymes A and B can be secreted directly from the CTL via the constitutive secretory pathway as shown by granzyme A enzymatic activity and immunoblots of secreted granzyme B, where one third of the protein fails to acquire the granule targeting signal. Perforin is also secreted via the constitutive pathway, both from the natural killer cell line, YT, and from CTL clones after TcR cross\u2010linking. Constitutive secretion of the lytic proteins can be blocked by both CHX and brefeldin A (BFA). While BFA does not affect the directional killing of recognized targets, it abrogates bystander killing, indicating that bystander killing arises from newly synthesized lytic proteins delivered via a non\u2010granule route.<\/jats:p><jats:p>These results demonstrate that the perforin\/granzyme\u2010mediated lytic pathway can be maintained while CTL kill multiple targets. We show that CTL not only re\u2010fill their granules during killing, but also secrete lytic proteins via a non\u2010granule\u2010mediated pathway.<\/jats:p>","DOI":"10.1002\/eji.1830250432","type":"journal-article","created":{"date-parts":[[2007,3,2]],"date-time":"2007-03-02T00:19:19Z","timestamp":1172794759000},"page":"1071-1079","source":"Crossref","is-referenced-by-count":178,"title":["Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re\u2010filling of the lytic granules and secretion of lytic proteins via a non\u2010granule pathway"],"prefix":"10.1002","volume":"25","author":[{"given":"Sylvie","family":"Isaaz","sequence":"first","affiliation":[]},{"given":"Kristin","family":"Baetz","sequence":"additional","affiliation":[]},{"given":"Kristin","family":"Olsen","sequence":"additional","affiliation":[]},{"given":"Eckhard","family":"Podack","sequence":"additional","affiliation":[]},{"given":"Gillian M.","family":"Griffiths","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2005,11,17]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2994224"},{"key":"e_1_2_1_3_2","first-page":"179","volume":"36","author":"Matter A.","year":"1979","journal-title":"Immunology"},{"key":"e_1_2_1_4_2","first-page":"37","volume":"2","author":"Kupfer A.","year":"1985","journal-title":"J. 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