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* Division of Clinical Pharmacology, University of Munich, Munich, Germany;
Junior Research Group NG2, Paul-Ehrlich-Institut, Langen, Germany;
Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, Germany;
Department of Obstetrics and Gynecology Maistrasse, University of Munich, Munich, Germany; and
¶ Department of Experimental Infection Research, Twincore–Center for Experimental and Clinical Infection Research, Hannover Medical School, Hannover, Germany
In the course of infection, the detection of pathogen-associated molecular patterns by specialized pattern recognition receptors in the host leads to activation of the innate immune system. Whereas the subsequent induction of adaptive immune responses in secondary lymphoid organs is well described, little is known about the effects of pathogen-associated molecular pattern-induced activation on primary lymphoid organs. Here we show that activation of innate immunity through the virus-sensing melanoma differentiation-associated gene 5 (MDA-5) receptor causes a rapid involution of the thymus. We observed a strong decrease in thymic cellularity associated with characteristic alterations in thymic subpopulations and microanatomy. In contrast, immune stimulation with potent TLR agonists did not lead to thymic involution or induce changes in thymic subpopulations, demonstrating that thymic pathology is not a general consequence of innate immune activation. We determined that suppression of thymocyte proliferation and enhanced apoptosis are the essential cellular mechanisms involved in the decrease in thymic size upon MDA-5 activation. Further, thymic involution critically depended on type I IFN. Strikingly however, no direct action of type I IFN on thymocytes was required, given that the decrease in thymic size was still observed in mice with a selective deletion of the type I IFN receptor on T cells. All changes observed were self-limiting, given that cessation of MDA-5 activation led to a rapid recovery of thymic size. We show for the first time that the in vivo activation of the virus-sensing MDA-5 receptor leads to a rapid and reversible involution of the thymus.
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1 This study was supported by grants from the Ludwig-Maximilians-Universität München Excellent Research Professorship (to S.E.), from the Else-Kröner Fresenius Foundation (to S.E. and C.B.), and from German Research Foundation Grants DFG En 169/7-2 and Graduiertenkolleg 1202 (to S.E. and C.B.), Excellence Cluster CIPSM 114 (to S.E.), BA3544/1-1 (to W.B.), and SFB-TR 36 (to S.E.). This work is part of the doctoral thesis of R.T. and N.S. supported by Graduiertenkolleg 1202.
2 D.A. and R.T. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Stefan Endres, Division of Clinical Pharmacology, Ludwig-Maximilians Universität, Ziemssenstrasse 1, 80336 Munich. E-mail address: endres{at}lmu.de
4 Abbreviations used in this paper: MDA-5, melanoma differentiation-associated gene 5; RIG-I, retinoic acid-inducible gene I; IFNAR, type I IFN receptor; poly(I:C), polyinosinic-polycytidylic acid; DN, double negative; DP, double positive; TEC, thymic epithelial cells.
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