title: Interleukin-21 accelerates thymic recovery from glucocorticoïd-induced atrophy.
abstract: Both physiological and psychological stress cause thymic atrophy via glucocorticoïd (GC)-dependent apoptosis of double-positive (DP) thymocytes. Given the pervasiveness of stress, GC-induced thymic atrophy is arguably the most common type of acquired immunodeficiency. We recently reported that interleukin-21 (IL-21) has a unique ability to expand the small subset of DP thymocytes (CD69(+)) which are ongoing positive selection, and that administration of IL-21 increases thymic output in aged mice. The goal of this study was to evaluate whether IL-21 could mitigate GC-induced thymic atrophy. In contrast to double-negative (DN) and single-positive (SP) thymocytes, most DP thymocytes (CD69(-)) do not constitutively express the IL-21 receptor (IL-21R). Accordingly, CD69(-) DP thymocytes from PBS-treated mice were unresponsive to IL-21 administration. However, following GC injection, surviving CD69(-) DP thymocytes up-regulated IL-21R and responded to IL-21 treatment as evidenced by enhancement of Bcl6 expression and phosphorylation of STAT1, STAT3 and STAT5. Consequently, IL-21 administration to GC-treated mice accelerated thymic recovery by expanding considerably DP thymocytes and, to a lesser extent, DN thymocytes. However, IL-21-induced expansion of DN/DP thymocytes did not alter the diversity of the intrathymic or peripheral T-cell receptor (TCR) repertoire. We conclude that IL-21 dramatically accelerates recovery from GC-induced thymic atrophy.
authors.affiliation: Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Moutih
authors.initials: M
authors.lastname: Rafei
authors.forename: Maude
authors.initials: M
authors.lastname: Dumont-Lagacé
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rouette
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
mesh_terms: D000818:Animals; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D060168:Thymocytes / Q000187:drug effects* / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D005938:Glucocorticoids; D007378:Interleukins; D053655:Receptors, Interleukin-21; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D000098546:Interleukin-21
references.citation: Eur J Immunol. 2012 May;42(5):1073-9
references.pmid: 22539280
references.citation: J Biol Chem. 2010 Nov 19;285(47):36698-708
references.pmid: 20847043
references.citation: J Leukoc Biol. 2008 Oct;84(4):915-23
references.pmid: 18495786
references.citation: Nat Rev Immunol. 2011 May;11(5):307-17
references.pmid: 21475308
references.citation: Environ Health Perspect. 2011 Mar;119(3):371-6
references.pmid: 21041162
references.citation: Annu Rev Immunol. 2000;18:309-45
references.pmid: 10837061
references.citation: J Immunol. 2005 Mar 15;174(6):3765-72
references.pmid: 15749917
references.citation: Blood. 2010 Feb 4;115(5):975-84
references.pmid: 19965633
references.citation: Blood. 2006 Dec 1;108(12):3777-85
references.pmid: 16896157
references.citation: Blood. 2009 May 28;113(22):5536-48
references.pmid: 19307668
references.citation: Brain Behav Immun. 2011 Feb;25(2):340-8
references.pmid: 20974245
references.citation: PLoS One. 2011;6(11):e27580
references.pmid: 22110677
references.citation: J Immunol. 1994 May 15;152(10):5014-21
references.pmid: 8176219
references.citation: Am J Clin Pathol. 1985 Jul;84(1):85-95
references.pmid: 4014079
references.citation: J Clin Oncol. 2008 Apr 20;26(12):2034-9
references.pmid: 18347008
references.citation: Blood. 1999 Apr 1;93(7):2282-96
references.pmid: 10090938
references.citation: Arch Biochem Biophys. 1989 Feb 15;269(1):365-70
references.pmid: 2537063
references.citation: Blood. 2003 Feb 15;101(4):1220-35
references.pmid: 12393483
references.citation: J Immunol. 2006 Feb 1;176(3):1695-702
references.pmid: 16424199
references.citation: J Leukoc Biol. 2008 Aug;84(2):348-56
references.pmid: 18467657
references.citation: Nat Immunol. 2000 Sep;1(3):214-20
references.pmid: 10973278
references.citation: Blood. 2011 Nov 10;118(19):5163-73
references.pmid: 21937690
references.citation: Blood. 2007 Aug 15;110(4):1161-7
references.pmid: 17456721
references.citation: Immunol Rev. 2012 May;247(1):172-83
references.pmid: 22500840
references.citation: Immunity. 2002 Dec;17(6):749-56
references.pmid: 12479821
references.citation: Science. 2002 Nov 22;298(5598):1630-4
references.pmid: 12446913
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3043-7
references.pmid: 8610165
references.citation: Blood. 2003 Apr 15;101(8):2914-23
references.pmid: 12515714
references.citation: Crit Rev Immunol. 2008;28(5):441-66
references.pmid: 19166388
references.citation: Immunity. 2000 Aug;13(2):199-212
references.pmid: 10981963
references.citation: J Immunol. 2003 Mar 1;170(5):2435-41
references.pmid: 12594267
references.citation: PLoS One. 2011 Mar 18;6(3):e17940
references.pmid: 21437240
references.citation: Nat Rev Immunol. 2009 Jul;9(7):480-90
references.pmid: 19543225
references.citation: Stress. 2012 Sep;15(5):472-8
references.pmid: 22845714
references.citation: Clin Cancer Res. 2007 Jun 15;13(12):3630-6
references.pmid: 17575227
references.citation: Nature. 1980 Apr 10;284(5756):555-6
references.pmid: 6245367
references.citation: Annu Rev Immunol. 2007;25:649-79
references.pmid: 17291187
references.citation: Psychosom Med. 2010 Oct;72(8):823-32
references.pmid: 20716708
references.citation: Int J Hematol. 2006 Oct;84(3):224-30
references.pmid: 17050196
references.citation: Cell Immunol. 1986 Jun;100(1):112-8
references.pmid: 3742599
references.citation: J Leukoc Biol. 2010 May;87(5):857-67
references.pmid: 20103765
references.citation: Blood. 2013 Jan 3;121(1):107-17
references.pmid: 23043071
references.citation: Annu Rev Immunol. 2008;26:57-79
references.pmid: 17953510
references.citation: Nat Immunol. 2013 Apr;14(4):380-8
references.pmid: 23455674
references.citation: Annu Rev Med. 1979;30:375-404
references.pmid: 95575
references.citation: J Clin Invest. 1999 Oct;104(8):1051-9
references.pmid: 10525043
references.citation: Rejuvenation Res. 2011 Jun;14(3):241-8
references.pmid: 21453014
references.citation: J Immunol. 2005 Aug 15;175(4):2321-30
references.pmid: 16081802
references.citation: Blood. 2013 May 30;121(22):4551-4
references.pmid: 23476051
references.citation: Cancer Lett. 2013 Apr 30;331(1):24-34
references.pmid: 23340174
references.citation: Br J Nutr. 2007 Oct;98 Suppl 1:S11-6
references.pmid: 17922946