TL1A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice  

作　　者：Mario Ruiz Pérez Christian Maueröder Wolf Steels Bruno Verstraeten Sahine Lameire Wei Xie Laura Wyckaert Jelle Huysentruyt Tatyana Divert Ria Roelandt Amanda Gonçalves Riet De Rycke Kodi Ravichandran Bart N.Lambrecht Tom Taghon Georges Leclercq Peter Vandenabeele Peter Tougaard 

机构地区：[1]Molecular Signaling and Cell Death Unit,VIB-UGent Center for Inflammation Research,Flanders Institute for Biotechnology,Ghent,Belgium [2]Department of Biomedical Molecular Biology,Ghent University,Ghent,Belgium [3]Cell Clearance in Health and Disease Lab,VIB-UGent Center for Inflammation Research,Flanders Institute for Biotechnology,Ghent,Belgium [4]Laboratory of Immunoregulation and Mucosal Immunology,VIB-UGent Center for Inflammation Research,Ghent,Belgium [5]Department of Internal Medicine and Pediatrics,Ghent University,Ghent,Belgium [6]VIB Single Cell Facility,Flanders Institute for Biotechnology,Ghent,Belgium [7]VIB BioImaging Core,VIB-UGent Center for Inflammation Research,Technologiepark-Zwijnaarde 71,Ghent,9052,Belgium [8]Department of Microbiology,Immunology,and Cancer Biology,University of Virginia,Charlottesville,VA,USA [9]Division of Immunobiology,Department of Pathology and Immunology,Washington University School of Medicine,St.Louis,MO,USA [10]Department of Pulmonary Medicine,Erasmus MC,Rotterdam,The Netherlands [11]Cancer Research Institute Ghent,Ghent,Belgium [12]Department of Diagnostic Sciences,Ghent University,Ghent,Belgium

出　　处：《Cellular & Molecular Immunology》2024年第8期807-825,共19页中国免疫学杂志（英文版）

基　　金：FWO Research Grants G.0B96.20N(PV,PT),G.0C76.18N(PV),G.0B71.18N(PV);G.0A93.22N(PV);Special Research Fund UGent(Methusalem grant BOF16/MET_V/007(PV);BOF22/MET_V/007(PV);iBOF ATLANTIS grant 20/IBF/039(PV));EOS MODEL-IDI Grant(30826052)(PV);EOS CD-INFLADIS(40007512)(PV);Foundation against Cancer(F/2016/865,F/2020/1505)(PV).FWO fundamental research fellowship PhD grant(MRP)(11A7222N);FWO senior postdoctoral fellowship(CM)(12Y2122N);DFG research fellowship(CM)(MA 7770/1-1);Cancer Research Institute Ghent(CRIG)consortia;Ghent Gut Inflammation Group(GGIG)consortia.Flanders Institute for Biotechnology(VIB).

摘　　要：Acute systemic inflammation critically alters the function of the immune system,often promoting myelopoiesis at the expense of lymphopoiesis.In the thymus,systemic inflammation results in acute thymic atrophy and,consequently,impaired T-lymphopoiesis.The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear.Here,we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis.The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus(MCMV)or pneumonia virus of mice(PVM).In vivo administration of TL1A and IL-18 induced acute thymic atrophy,while thymic neutrophils expanded.Fate mapping with Ms4a3-Cre mice demonstrated that thymic neutrophils emerge from thymic granulocyte-monocyte progenitors(GMPs),while Rag1-Cre fate mapping revealed a common developmental path with lymphocytes.These effects could be modeled ex vivo using neonatal thymic organ cultures(NTOCs),where TL1A and IL-18 synergistically enhanced neutrophil production and egress.NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture,indicating that NOTCH restricted steady-state thymic granulopoiesis.To promote myelopoiesis,TL1A,and IL-18 synergistically increased GM-CSF levels in the NTOC,which was mainly produced by thymic ILC1s.In support,TL1A-and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/-mice and by GM-CSFR antibody blockade,revealing that GM-CSF is the essential factor driving thymic granulopoiesis.Taken together,our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner.

关 键 词：Thymic Neutrophils Emergency granulopoiesis Thymus atrophy Thymic GMP Cytokine synergy 

分 类 号：R392[医药卫生—免疫学]