{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:24:25Z","timestamp":1791271465320,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"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":[[2015,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV). Twp CD8+ T cells showed impaired polyfunctional cytokine production, whereas cytotoxicity as the crucial antiviral effector function for LCMV control was normal. The main limiting factor in the antiviral response of twp mice was impaired T cell proliferation and survival, leading to a 5- to 10-fold reduction of antiviral T cells at the peak of the immune response. This was still sufficient to control infection with the LCMV Armstrong strain, but the more rapidly replicating LCMV-WE induced T cell exhaustion and viral persistence. Thus, under conditions of impaired TCR signaling, reduced T cell expansion was the limiting factor in antiviral immunity. These findings have implications for understanding antiviral immunity in patients with T cell deficiencies.<\/jats:p>","DOI":"10.4049\/jimmunol.1400328","type":"journal-article","created":{"date-parts":[[2015,2,12]],"date-time":"2015-02-12T06:11:17Z","timestamp":1423721477000},"page":"2725-2734","source":"Crossref","is-referenced-by-count":7,"title":["T Cell Expansion Is the Limiting Factor of Virus Control in Mice with Attenuated TCR Signaling: Implications for Human Immunodeficiency"],"prefix":"10.1093","volume":"194","author":[{"given":"Kristina M","family":"Hillen","sequence":"first","affiliation":[{"name":"Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg , 79106 Freiburg ,","place":["Germany"]},{"name":"Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"Faculty of Biology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"BIOSS Centre for Biological Signalling Studies, University of Freiburg , 79104 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Gather","sequence":"additional","affiliation":[{"name":"Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg , 79106 Freiburg ,","place":["Germany"]},{"name":"Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"Faculty of Biology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"BIOSS Centre for Biological Signalling Studies, University of Freiburg , 79104 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anselm","family":"Enders","sequence":"additional","affiliation":[{"name":"Ramaciotti Immunization Genomics Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University , Canberra, Acton 2601, Australian Capital Territory ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanspeter","family":"Pircher","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aichele","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Fisch","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Freiburg , 79106 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Blumenthal","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Freiburg , 79106 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang W","family":"Schamel","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Freiburg , 79106 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Straub","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"Faculty of Biology, University of Freiburg , 79104 Freiburg ,","place":["Germany"]},{"name":"BIOSS Centre for Biological Signalling Studies, University of Freiburg , 79104 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C","family":"Goodnow","sequence":"additional","affiliation":[{"name":"Department of Immunology, John Curtin School of Medical Research, The Australian National University , Canberra, Acton 2601, Australian Capital Territory ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[{"name":"Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg , 79106 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,3,15]]},"reference":[{"key":"2025030705262639100_r1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1600-065X.2009.00843.x","article-title":"Organization of proximal signal initiation at the TCR:CD3 complex","volume":"232","author":"Guy","year":"2009","journal-title":"Immunol. 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Engl. J. Med."},{"key":"2025030705262639100_r8","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1097\/01.all.0000191886.12645.79","article-title":"CD3 deficiencies","volume":"5","author":"Fischer","year":"2005","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"2025030705262639100_r9","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1126\/science.8202713","article-title":"ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency","volume":"264","author":"Chan","year":"1994","journal-title":"Science"},{"key":"2025030705262639100_r10","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.jaci.2012.07.029","article-title":"Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency","volume":"130","author":"Hauck","year":"2012","journal-title":"J. Allergy Clin. 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Immunol."},{"key":"2025030705262639100_r16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.clim.2011.05.007","article-title":"Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency","volume":"141","author":"Felgentreff","year":"2011","journal-title":"Clin. Immunol."},{"key":"2025030705262639100_r17","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature"},{"key":"2025030705262639100_r18","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0166-0934(91)90018-U","article-title":"Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates","volume":"33","author":"Battegay","year":"1991","journal-title":"J. Virol. 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Immunol."},{"key":"2025030705262639100_r24","doi-asserted-by":"crossref","first-page":"5560","DOI":"10.1182\/blood-2010-06-292458","article-title":"Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells","volume":"116","author":"Wiehagen","year":"2010","journal-title":"Blood"},{"key":"2025030705262639100_r25","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/362758a0","article-title":"Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells","volume":"362","author":"Moskophidis","year":"1993","journal-title":"Nature"},{"key":"2025030705262639100_r26","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/364798a0","article-title":"Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes","volume":"364","author":"Rothe","year":"1993","journal-title":"Nature"},{"key":"2025030705262639100_r27","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.1995.tb00090.x","article-title":"Immune defence in mice lacking type I and\/or type II interferon receptors","volume":"148","author":"van den Broek","year":"1995","journal-title":"Immunol. 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