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Regulated expression of nuclear receptor ROR?t confers distinct functional fates to NK cell receptor-expressing ROR?t(+) innate lymphocytes.

ABSTRACT: Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor ROR?t is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKR?ROR?t(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)ROR?t(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was characterized by the stable upregulation of NKRs and a progressive loss of ROR?t expression. Whereas interleukin-7 (IL-7) and intestinal microbiota stabilized ROR?t expression within such NKR-LTi cells, IL-12 and IL-15 accelerated ROR?t loss. ROR?t(+) NKR-LTi cells produced IL-22, whereas ROR?t? NKR-LTi cells released IFN-? and were potent inducers of colitis. Thus, the ROR?t gradient in NKR-LTi cells serves as a tunable rheostat for their functional program. Our data also define a previously unappreciated role of ROR?t? NKR-LTi cells for the onset or maintenance of inflammatory bowel diseases.

SUBMITTER: Vonarbourg C

PROVIDER: S-EPMC3042726 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt(+) innate lymphocytes.

Vonarbourg Cedric C Mortha Arthur A Bui Viet L VL Hernandez Pedro P PP Kiss Elina A EA Hoyler Thomas T Flach Melanie M Bengsch Bertram B Thimme Robert R Hölscher Christoph C Hönig Manfred M Pannicke Ulrich U Schwarz Klaus K Ware Carl F CF Finke Daniela D Diefenbach Andreas A

Immunity 20101101 5

Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor RORγt is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKR⁻RORγt(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)RORγt(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was charac ...[more]

PMID: 21093318

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Project description:AimsRetinoic acid receptor-related orphan nuclear receptor ?t (ROR?t) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that ROR?t plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of ROR?t in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of ROR?t and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that ROR?t-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that ROR?t-expressing cells were released from the spleen at day 1 after MI. Though ROR?t-expressing cells in spleen expressed ??TCR or CD4, ??TCR+ cells were major population of ROR?t-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of ROR?t-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at ROR?t locus (ROR?t+/- mice), which physiologically showed reduced expression of ROR?t mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in ROR?t+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in ROR?t+/- mice 7 days after MI (Injured area: ROR?t+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: ROR?t+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: ROR?t+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in ROR?t+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of ROR?t, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in ROR?t+/- hearts.ConclusionsHeterozygous deletion of ROR?t gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that ROR?t-expressing cells contribute to tissue repair in infarcted myocardium.

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Regulated expression of nuclear receptor ROR?t confers distinct functional fates to NK cell receptor-expressing ROR?t(+) innate lymphocytes.

Publications

Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt(+) innate lymphocytes.

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