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Rapid Involution of the Thymus Differentiation-Associated Gene 5

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Rapid Involution of the Thymus Differentiation-Associated Gene 5 Activation of Melanoma Differentiation-Associated Gene 5 Causes Rapid Involution of the Thymus This information is current as David Anz, Raffael Thaler, Nicolas Stephan, Zoe Waibler, of October 1, 2021. Michael J. Trauscheid, Christoph Scholz, Ulrich Kalinke, Winfried Barchet, Stefan Endres and Carole Bourquin J Immunol 2009; 182:6044-6050; ; doi: 10.4049/jimmunol.0803809 http://www.jimmunol.org/content/182/10/6044 Downloaded from References This article cites 53 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/182/10/6044.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Activation of Melanoma Differentiation-Associated Gene 5 Causes Rapid Involution of the Thymus1 David Anz,2* Raffael Thaler,2* Nicolas Stephan,* Zoe Waibler,† Michael J. Trauscheid,‡ Christoph Scholz,*§ Ulrich Kalinke,¶ Winfried Barchet,‡ Stefan Endres,3* and Carole Bourquin* 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2009, 182: 6044–6050. he innate immune system represents the first line of de- RIG-I recognizes viral ssRNA with a 5Ј-triphosphate motif and fense against viral infections. Initiation of antiviral im- short dsRNA, MDA-5 is activated by long dsRNA (3–5). Vi- T mune responses is critically dependent on the activation rally encoded RNA can also be detected by another family of of innate pattern recognition receptors that recognize evolutionar- pattern recognition receptors, the TLRs; long dsRNA and ss- ily conserved structures, termed pathogen-associated molecular RNA sequences can activate innate immunity through the en- patterns (1). In particular, the cytoplasmic helicases melanoma dif- dosomally located TLR3 and TLR7, respectively (6–10). Stim- by guest on October 1, 2021 ferentiation-associated gene 5 (MDA-5)4 and retinoic acid induc- ulation of pattern recognition receptors leads to the initiation of ible gene I (RIG-I) play an essential role in sensing viral RNA and an innate immune response characterized by the production of in generating immune responses to RNA viruses (2–4). Whereas a large panel of proinflammatory cytokines (7, 11). Among these, the type I IFNs IFN-␣ and IFN-␤ play an essential role in preventing viral spread through the induction of apoptosis and *Division of Clinical Pharmacology, University of Munich, Munich, Germany; †Jun- ior Research Group NG2, Paul-Ehrlich-Institut, Langen, Germany; ‡Institute of Clin- the suppression of cell proliferation (12, 13). In secondary lym- ical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, phoid organs such as the spleen, the lymph nodes, or the GALT, Germany; §Department of Obstetrics and Gynecology Maistrasse, University of Mu- nich, Munich, Germany; and ¶Department of Experimental Infection Research, Twin- stimulation by pathogen-associated molecular patterns leads to core–Center for Experimental and Clinical Infection Research, Hannover Medical the generation of adaptive T and B cell responses against School, Hannover, Germany pathogens. Received for publication November 13, 2008. Accepted for publication March In contrast to the well-characterized effects of pattern recog- 11, 2009. nition receptor activation in secondary lymphoid organs, the The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance consequences of innate immune activation on the primary lym- with 18 U.S.C. Section 1734 solely to indicate this fact. phoid organs, the bone marrow and thymus, are still unclear. 1 This study was supported by grants from the Ludwig-Maximilians-Universita¨t Within these organs, continuous proliferation of pluripotent Mu¨nchen Excellent Research Professorship (to S.E.), from the Else-Kro¨ner Fresenius progenitors is necessary to supply the organism with immune 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 cells and to maintain organ integrity. In the bone marrow, pro- 114 (to S.E.), BA3544/1-1 (to W.B.), and SFB-TR 36 (to S.E.). This work is part of liferation is suppressed during viral infections, an effect that is the doctoral thesis of R.T. and N.S. supported by Graduiertenkolleg 1202. in part mediated by the antiproliferative action of type I IFN 2 D.A. and R.T. contributed equally to this study. (14). Indeed, neutropenia, a hallmark of bone marrow suppres- 3 Address correspondence and reprint requests to Dr. Stefan Endres, Division of Clin- sion, is one of the most common side effects of IFN-␣ treatment ical Pharmacology, Ludwig-Maximilians Universita¨t, Ziemssenstrasse 1, 80336 Mu- nich. E-mail address: [email protected] in hepatitis C-infected patients (15, 16). 4 Abbreviations used in this paper: MDA-5, melanoma differentiation-associated gene Little is known about the impact of innate immune activation on 5; RIG-I, retinoic acid-inducible gene I; IFNAR, type I IFN receptor; poly(I:C), poly- structure and function of the thymus in vivo. The development of inosinic-polycytidylic acid; DN, double negative; DP, double positive; TEC, thymic T cells from bone marrow progenitors takes place exclusively in epithelial cells. the thymus, and an efficient thymic output of lymphocytes is there- Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 fore crucial for the maintenance of the naive T cell pool in the www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803809 The Journal of Immunology 6045 periphery (17–19). An important fraction of self-reactive T cells is sions of thymus and spleen were washed twice with PBS before resuspen- deleted in the thymus by apoptosis, and thymic cellularity is main- sion in the provided buffer and incubation with annexin V and propidium tained by vigorous proliferation of immature thymocytes. Viral iodide. Cells were subsequently analyzed by flow cytometry. infections are in some cases associated with in vivo alterations of Statistical analysis thymic function; thymic atrophy and a reduced T cell output are All data are presented as mean Ϯ SEM and were analyzed as appropriate seen in HIV-infected patients (20) and have also been described in by the unpaired Student t test or the ANOVA test. Statistical analysis was a mouse model of reovirus infection (21). The mechanisms in- performed using SPSS software. volved remain, however, unclear. We describe here for the first time that in vivo activation of the virus-sensing MDA-5 receptor Results causes involution of the thymus. Stimulation of innate immunity through MDA-5 causes involution of the thymus Materials and Methods To investigate whether in vivo activation of innate immunity af- Mice fects the thymus, we treated mice with the dsRNA molecule Female C57BL/6 and BALB/c mice were purchased from Harlan-Winkel- poly(I:C). Poly(I:C) stimulates the immune system through two mann. Experiments were done on C57BL/6 mice unless indicated other- different pathways mediated by activation of either the endosomal Ϫ/Ϫ wise. Type I IFN receptor-deficient mice (IFNAR ) were backcrossed TLR3 or the cytoplasmic helicases RIG-I and MDA-5 (4–6, 24). 20 times on the C57BL/6 background (22). CD4creϩ/ϪIFNARflox/flox mice, ϩ Ϫ Ϫ Ϫ Adult mice were injected twice with poly(I:C) at 3-day intervals, CD19cre / IFNARflox/flox, and MDA-5 / mice have been previously de- scribed (23, 24). Mice were at least 8 wk of age at the onset of experiments.
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