{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:57:42Z","timestamp":1789109862657,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Prolonged immunosuppression and hypoinflammation, termed compensatory anti-inflammatory response syndrome (CARS), contribute to high morbidity and mortality in the late phase of sepsis. Although apoptosis is a well-known cause of lymphopenia in sepsis, the contribution of thymic output to immune alterations in sepsis and potential compensatory mechanisms are largely unknown. Methods: We investigate the release of CD4+ T cells from the thymus and their peripheral proliferation by evaluating T-cell receptor excision circles (TREC) and the expression of CD31 as markers for recent thymic emigrants (RTE) and their proliferative offspring in septic patients with relevant lymphopenia in the CARS phase. Moreover, we determine the aging of T cells by measuring telomere characteristics. Results: In septic patients, we found decreased CD4+ T-helper cell numbers, while CD8+ T cell numbers were unchanged. As a possible cause, we detected increased apoptosis of CD4+ T-helper cells and decreased levels of IL-7, which promotes the maturation of T cells in the thymus. Accordingly, the relative number of mature CD4+ T cells, TREC-containing CD4+ T cells, and CD31+ RTEs (characteristic of thymic output) was decreased, while the relative number of CD31-T cells (peripherally expanded na\u00efve T cells) was increased. Furthermore, the telomere length decreased, although telomerase activity and markers for the shelterin complex were increased specifically in CD4+ but not in CD8+ T cells. Conclusion: We thus conclude that, in addition to T-cell apoptosis, decreased thymic output and increased aging of CD4+ T cells may contribute to lymphopenia and immunosuppression in sepsis. Increased proliferation of peripheral T cells cannot compensate for these effects.<\/jats:p>","DOI":"10.3390\/jcm9092695","type":"journal-article","created":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T21:13:42Z","timestamp":1597958022000},"page":"2695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Decreased Thymic Output Contributes to Immune Defects in Septic Patients"],"prefix":"10.3390","volume":"9","author":[{"given":"Natascha","family":"Sommer","sequence":"first","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Noack","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hecker","sequence":"additional","affiliation":[{"name":"Department of General and Thoracic Surgery, Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Hackstein","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, 91054 Erlangen, Germany"},{"name":"Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7571-8362","authenticated-orcid":false,"given":"Gregor","family":"Bein","sequence":"additional","affiliation":[{"name":"Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2675-3871","authenticated-orcid":false,"given":"Norbert","family":"Weissmann","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6565-2187","authenticated-orcid":false,"given":"Konstantin","family":"Mayer","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"},{"name":"Department of Pulmonary and Sleep Medicine, ViDia hospitals, 76137 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hecker","sequence":"additional","affiliation":[{"name":"Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University of Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1097\/CCM.0b013e31827c09f8","article-title":"Benchmarking the Incidence and Mortality of Severe Sepsis in the United States","volume":"41","author":"Gaieski","year":"2013","journal-title":"Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ccm.2016.01.002","article-title":"The Changing Epidemiology and Definitions of Sepsis","volume":"37","author":"Kempker","year":"2016","journal-title":"Clin. Chest Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1189\/jlb.5MR0114-067R","article-title":"Impact of sepsis on CD4 T cell immunity","volume":"96","author":"Condotta","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nri3552","article-title":"Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy","volume":"13","author":"Hotchkiss","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.4049\/jimmunol.177.3.1967","article-title":"Circulating cytokine\/inhibitor profiles reshape the understanding of the SIRS\/CARS continuum in sepsis and predict mortality","volume":"177","author":"Osuchowski","year":"2006","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1084\/jem.20111354","article-title":"A genomic storm in critically injured humans","volume":"208","author":"Xiao","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1186\/cc10332","article-title":"The late phase of sepsis is characterized by an increased microbiological burden and death rate","volume":"15","author":"Otto","year":"2011","journal-title":"Crit. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1097\/00003246-199907000-00002","article-title":"Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction","volume":"27","author":"Hotchkiss","year":"1999","journal-title":"Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6952","DOI":"10.4049\/jimmunol.166.11.6952","article-title":"Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans","volume":"166","author":"Hotchkiss","year":"2001","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/SHK.0000000000000234","article-title":"Persistent Lymphopenia After Diagnosis of Sepsis Predicts Mortality","volume":"42","author":"Drewry","year":"2014","journal-title":"Shock"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13613-017-0242-0","article-title":"Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission","volume":"7","author":"Adrie","year":"2017","journal-title":"Ann. Intensive Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00134-012-2769-8","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012","volume":"39","author":"Dellinger","year":"2013","journal-title":"Intensive Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ddmec.2008.02.010","article-title":"Role of Programmed Cell Death in the Immunopathogenesis of Sepsis","volume":"4","author":"Perl","year":"2007","journal-title":"Drug Discov. Today Dis. Mech."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.bbalip.2018.06.011","article-title":"Resolvin E1 and its precursor 18 R -HEPE restore mitochondrial function in inflammation","volume":"1863","author":"Hecker","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/30.10.e47","article-title":"Telomere measurement by quantitative PCR","volume":"30","author":"Cawthon","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ponchel, F., Toomes, C., Bransfield, K., Leong, F.T., Douglas, S.H., Field, S.L., Bell, S.M., Combaret, V., Puisieux, A., and Mighell, A.J. (2003). Real-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol., 3.","DOI":"10.1186\/1472-6750-3-18"},{"key":"ref_18","first-page":"1","article-title":"PPAR-\u03b1 activation reduced LPS-induced inflammation in alveolar epithelial cells","volume":"2148","author":"Hecker","year":"2015","journal-title":"Exp. Lung Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s13054-015-0933-6","article-title":"Immunomodulation by lipid emulsions in pulmonary inflammation: A randomized controlled trial","volume":"19","author":"Hecker","year":"2015","journal-title":"Crit. Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"R158","DOI":"10.1186\/cc10293","article-title":"Post-operative infection and sepsis in humans is associated with deficient gene expression of \u03b3c cytokines and their apoptosis mediators","volume":"15","author":"White","year":"2011","journal-title":"Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e83","DOI":"10.1016\/j.jss.2011.12.003","article-title":"The postoperative serum interleukin-15 concentration correlates with organ dysfunction and the prognosis of septic patients following emergency gastrointestinal surgery","volume":"175","author":"Kimura","year":"2012","journal-title":"J. Surg. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.4049\/jimmunol.1601486","article-title":"IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function","volume":"198","author":"Guo","year":"2017","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.21037\/jtd.2019.12.63","article-title":"The complete blood count to diagnose septic shock","volume":"12","author":"Farkas","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1046\/j.1469-0691.2003.00518.x","article-title":"Lymphocyte subset numbers depend on the bacterial origin of sepsis","volume":"9","author":"Holub","year":"2003","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/S0140-6736(00)02293-5","article-title":"Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution","volume":"355","author":"Douek","year":"2000","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ni0203-97","article-title":"Thymic output: A bad TREC record","volume":"4","author":"Hazenberg","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e98960","DOI":"10.1172\/jci.insight.98960","article-title":"Interleukin-7 restores lymphocytes in septic shock: The IRIS-7 randomized clinical trial","volume":"3","author":"Francois","year":"2018","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1097\/ACI.0b013e32834c233a","article-title":"T-cell receptor excision circles in primary immunodeficiencies and other T-cell immune disorders","volume":"11","author":"Somech","year":"2011","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ammer-Herrmenau, C., Kulkarni, U., Andreas, N., Ungelenk, M., Ravens, S., H\u00fcbner, C., Kather, A., Kurth, I., Bauer, M., and Kamradt, T. (2019). Sepsis induces long-lasting impairments in CD4+ T-cell responses despite rapid numerical recovery of T-lymphocyte populations. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211716"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tomino, A., Tsuda, M., Aoki, R., Kajita, Y., Hashiba, M., Terajima, T., Kano, H., and Takeyama, N. (2017). Increased PD-1 Expression and Altered T Cell Repertoire Diversity Predict Mortality in Patients with Septic Shock: A Preliminary Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169653"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/CCM.0b013e3182657948","article-title":"Decreased T-cell repertoire diversity in sepsis: A preliminary study","volume":"41","author":"Venet","year":"2013","journal-title":"Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.immuni.2012.02.006","article-title":"Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans","volume":"36","author":"Mugwagwa","year":"2012","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.4049\/jimmunol.1701618","article-title":"Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity","volume":"200","author":"Jensen","year":"2018","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1097\/00024382-199704000-00002","article-title":"Cecal Ligation and Puncture (CLP) Induces Apoptosis in Thymus, Spleen, Lung, and Gut by an Endotoxin and TNF-independent Pathway","volume":"7","author":"Hiramatsu","year":"1997","journal-title":"Shock"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1189\/jlb.0808491","article-title":"Differential lymphopenia-induced homeostatic proliferation for CD4+ and CD8+ T cells following septic injury","volume":"85","author":"Unsinger","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_36","first-page":"341","article-title":"Thymic output: Influence factors and molecular mechanism","volume":"3","author":"Jin","year":"2006","journal-title":"Cell. Mol. Immunol."},{"key":"ref_37","first-page":"1680","article-title":"T cell replicative senescence in human aging","volume":"19","author":"Chou","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"886","DOI":"10.2119\/molmed.2016.00225","article-title":"Sepsis induces telomere shortening: A potential mechanism responsible for delayed pathophysiological events in sepsis survivors?","volume":"22","author":"Oliveira","year":"2017","journal-title":"Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2217\/imt.10.107","article-title":"Telomerase and primary T cells: Biology and immortalization for adoptive immunotherapy","volume":"3","author":"Barsov","year":"2011","journal-title":"Immunotherapy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/j.1365-2567.2006.02429.x","article-title":"Prolonged exposure of na\u00efve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length","volume":"119","author":"Wallace","year":"2006","journal-title":"Immunology"}],"updated-by":[{"DOI":"10.3390\/jcm11154497","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000}}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/9\/2695\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:54:35Z","timestamp":1754261675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/9\/2695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,20]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["jcm9092695"],"URL":"https:\/\/doi.org\/10.3390\/jcm9092695","relation":{"correction":[{"id-type":"doi","id":"10.3390\/jcm11154497","asserted-by":"object"}]},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,20]]}}}