{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:39:28Z","timestamp":1790368768252,"version":"4.1.0"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"10","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,9,23]]},"abstract":"<jats:p>Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GRlck-Cre) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GRlck-Cre mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-\u03b3 and TNF production in vivo. Unexpectedly, these CD4+ T lymphocytes also overexpressed IL-10. Importantly, CD4+ T cell depletion in wild-type or GRlck-Cre mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG\u2212\/\u2212 animals, adoptive transfer of CD4+ T lymphocytes was required for GC induction. These findings establish a novel IL-10\u2013independent immunomodulatory circuit in which CD4+ T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival.<\/jats:p>","DOI":"10.1084\/jem.20122300","type":"journal-article","created":{"date-parts":[[2013,8,27]],"date-time":"2013-08-27T03:20:31Z","timestamp":1377573631000},"page":"1919-1927","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection"],"prefix":"10.1084","volume":"210","author":[{"given":"David G.","family":"Kugler","sequence":"first","affiliation":[{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"},{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Mittelstadt","sequence":"additional","affiliation":[{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Ashwell","sequence":"additional","affiliation":[{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Sher","sequence":"additional","affiliation":[{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragana","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases 1 ; 2 ; and 3"},{"name":"Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute 1 ; 2 ; and 3"},{"name":"The Johns Hopkins University\/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892 1 ; 2 ; and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,8,26]]},"reference":[{"key":"2023072601213359400_bib1","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/S1074-7613(00)80596-8","article-title":"Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function","volume":"9","author":"Adachi","year":"1998","journal-title":"Immunity."},{"key":"2023072601213359400_bib2","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1084\/jem.20021183","article-title":"Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection","volume":"196","author":"Aliberti","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023072601213359400_bib3","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1146\/annurev.immunol.18.1.309","article-title":"Glucocorticoids in T cell development and function","volume":"18","author":"Ashwell","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"2023072601213359400_bib4","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1084\/jem.20011629","article-title":"In vitro generation of interleukin 10\u2013producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)\u2013 and Th2-inducing cytokines","volume":"195","author":"Barrat","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023072601213359400_bib5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/j.1600-065X.2011.01019.x","article-title":"Mechanisms of tolerance","volume":"241","author":"Bluestone","year":"2011","journal-title":"Immunol. Rev."},{"key":"2023072601213359400_bib6","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.mib.2007.09.013","article-title":"Rhoptries: an arsenal of secreted virulence factors","volume":"10","author":"Bradley","year":"2007","journal-title":"Curr. Opin. Microbiol."},{"key":"2023072601213359400_bib7","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.4049\/jimmunol.174.6.3148","article-title":"IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-\u03b1 in host macrophages","volume":"174","author":"Butcher","year":"2005","journal-title":"J. Immunol."},{"key":"2023072601213359400_bib8","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/35038103","article-title":"Development of Th1-type immune responses requires the type I cytokine receptor TCCR","volume":"407","author":"Chen","year":"2000","journal-title":"Nature."},{"key":"2023072601213359400_bib9","doi-asserted-by":"publisher","first-page":"2964","DOI":"10.1128\/IAI.00047-11","article-title":"Interleukin-10 and immunity against prokaryotic and eukaryotic intracellular pathogens","volume":"79","author":"Cyktor","year":"2011","journal-title":"Infect. Immun."},{"key":"2023072601213359400_bib10","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.4049\/jimmunol.164.4.1768","article-title":"Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes","volume":"164","author":"Franchimont","year":"2000","journal-title":"J. Immunol."},{"key":"2023072601213359400_bib11","doi-asserted-by":"crossref","first-page":"798","DOI":"10.4049\/jimmunol.157.2.798","article-title":"In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-\u03b3 and TNF-\u03b1","volume":"157","author":"Gazzinelli","year":"1996","journal-title":"J. Immunol."},{"key":"2023072601213359400_bib12","doi-asserted-by":"publisher","first-page":"3279","DOI":"10.1128\/IAI.00425-12","article-title":"The Toxoplasma gondii peptide AS15 elicits CD4 T cells that can control parasite burden","volume":"80","author":"Grover","year":"2012","journal-title":"Infect. Immun."},{"key":"2023072601213359400_bib13","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.immuni.2012.11.003","article-title":"Interleukin-27: balancing protective and pathological immunity","volume":"37","author":"Hunter","year":"2012","journal-title":"Immunity."},{"key":"2023072601213359400_bib14","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.chom.2010.01.010","article-title":"Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection","volume":"7","author":"Jamieson","year":"2010","journal-title":"Cell Host Microbe."},{"key":"2023072601213359400_bib15","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1084\/jem.20062175","article-title":"Conventional T-bet+Foxp3\u2212 Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection","volume":"204","author":"Jankovic","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072601213359400_bib16","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/mi.2010.8","article-title":"IL-10 production by CD4+ effector T cells: a mechanism for self-regulation","volume":"3","author":"Jankovic","year":"2010","journal-title":"Mucosal Immunol."},{"key":"2023072601213359400_bib17","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1096\/fj.06-7452com","article-title":"The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction","volume":"21","author":"Liberman","year":"2007","journal-title":"FASEB J."},{"key":"2023072601213359400_bib18","doi-asserted-by":"crossref","first-page":"5936","DOI":"10.4049\/jimmunol.174.10.5936","article-title":"Cutting edge: re-evaluating the in vivo cytokine responses of CD8+ T cells during primary and secondary viral infections","volume":"174","author":"Liu","year":"2005","journal-title":"J. Immunol."},{"key":"2023072601213359400_bib19","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.molmed.2007.02.001","article-title":"Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression","volume":"13","author":"L\u00f6wenberg","year":"2007","journal-title":"Trends Mol. Med."},{"key":"2023072601213359400_bib20","doi-asserted-by":"publisher","first-page":"7749","DOI":"10.1073\/pnas.1332767100","article-title":"T-bet is required for optimal production of IFN-\u03b3 and antigen-specific T cell activation by dendritic cells","volume":"100","author":"Lugo-Villarino","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072601213359400_bib21","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.1172\/JCI63067","article-title":"Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness","volume":"122","author":"Mittelstadt","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2023072601213359400_bib22","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.jneuroim.2011.03.010","article-title":"Immunoneuroendocrine alterations in patients with progressive forms of chronic Chagas disease","volume":"235","author":"P\u00e9rez","year":"2011","journal-title":"J. Neuroimmunol."},{"key":"2023072601213359400_bib23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0091-679X(08)61845-2","article-title":"Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii","volume":"45","author":"Roos","year":"1994","journal-title":"Methods Cell Biol."},{"key":"2023072601213359400_bib24","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.immuni.2009.03.013","article-title":"Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12","volume":"30","author":"Schulz","year":"2009","journal-title":"Immunity."},{"key":"2023072601213359400_bib25","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1084\/jem.20050433","article-title":"Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis","volume":"203","author":"Sionov","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023072601213359400_bib26","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/nri1810","article-title":"Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens","volume":"6","author":"Sternberg","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2023072601213359400_bib27","doi-asserted-by":"publisher","first-page":"e38233","DOI":"10.1371\/journal.pone.0038233","article-title":"A single E627K mutation in the PB2 protein of H9N2 avian influenza virus increases virulence by inducing higher glucocorticoids (GCs) level","volume":"7","author":"Tian","year":"2012","journal-title":"PLoS ONE."},{"key":"2023072601213359400_bib28","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/S1074-7613(03)00300-5","article-title":"The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection","volume":"19","author":"Villarino","year":"2003","journal-title":"Immunity."},{"key":"2023072601213359400_bib29","doi-asserted-by":"crossref","first-page":"8434","DOI":"10.4049\/jimmunol.180.12.8434","article-title":"Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis","volume":"180","author":"W\u00fcst","year":"2008","journal-title":"J. Immunol."},{"key":"2023072601213359400_bib30","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1084\/jem.189.7.1083","article-title":"Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-\u03b3\u2013 and tumor necrosis factor (TNF)-\u03b1\u2013dependent host resistance to the intracellular pathogen, Toxoplasma gondii","volume":"189","author":"Yap","year":"1999","journal-title":"J. Exp. Med."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/10\/1919\/1745906\/jem_20122300.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/10\/1919\/1745906\/jem_20122300.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T01:21:58Z","timestamp":1690334518000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/210\/10\/1919\/41418\/CD4-T-cells-are-trigger-and-target-of-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,26]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2013,9,23]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20122300","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2013,8,26]]}}}