Goblet cell-derived resistin-like molecule beta augments CD4+ T cell production of IFN-gamma and infection-induced intestinal inflammation.
The secreted goblet cell-derived protein resistin-like molecule beta (RELMbeta) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMbeta influences CD4(+) T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMbeta in augmenting CD4(+) Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-gamma production and intestinal inflammation. In contrast, infected RELMbeta(-/-) mice exhibited a significantly reduced expression of parasite-specific CD4(+) T cell-derived IFN-gamma and TNF-alpha and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMbeta activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-gamma expression in CD4(+) T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMbeta, can promote adaptive CD4(+) T cell responses and chronic inflammation following intestinal helminth infection.
Nair
Meera G
MG
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Guild
Katherine J
KJ
Du
Yurong
Y
Zaph
Colby
C
Yancopoulos
George D
GD
Valenzuela
David M
DM
Murphy
Andrew
A
Stevens
Sean
S
Karow
Margaret
M
Artis
David
D
D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002908:Chronic Disease; D020397:Goblet Cells / Q000276:immunology* / Q000378:metabolism; D006729:Hormones, Ectopic / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis*; D007411:Intestinal Diseases, Parasitic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052243:Resistin / Q000235:genetics / Q000502:physiology; D014257:Trichuriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014258:Trichuris / Q000276:immunology
D000276:Adjuvants, Immunologic; D006729:Hormones, Ectopic; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D052243:Resistin; C486522:Retnlb protein, mouse; D007371:Interferon-gamma
Biochem Biophys Res Commun. 2003 Oct 24;310(3):927-35
14550293
Nature. 2007 Mar 29;446(7135):557-61
17361131
Gastroenterology. 2006 Jul;131(1):117-29
16831596
Immunol Rev. 2004 Oct;201:75-88
15361234
Immunol Rev. 2004 Oct;201:139-55
15361238
Nat Med. 2006 Aug;12(8):955-60
16892038
J Immunol. 1997 Dec 15;159(12):6276-82
9550432
Nat Rev Immunol. 2003 Apr;3(4):331-41
12669023
Science. 2001 Dec 7;294(5549):2155-8
11739954
Science. 1996 Oct 11;274(5285):262-5
8824194
J Exp Med. 2001 Aug 6;194(3):355-64
11489954
J Immunol. 2003 May 1;170(9):4693-700
12707348
J Immunol. 1998 Apr 1;160(7):3453-61
9531306
Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13596-600
15340149
J Immunol. 2004 Nov 1;173(9):5626-34
15494513
Science. 2001 Jun 8;292(5523):1907-10
11397944
Eur J Immunol. 1997 Apr;27(4):866-70
9130637
Nature. 2007 Mar 29;446(7135):552-6
17322906
Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G1074-83
15576623
Science. 2005 Jan 14;307(5707):254-8
15653504
J Exp Med. 2007 Mar 19;204(3):481-7
17353366
Gastroenterology. 2003 Nov;125(5):1388-97
14598255
J Allergy Clin Immunol. 2006 Jul;118(1):257-68
16815164
J Immunol. 2007 Nov 15;179(10):7012-20
17982092
Nature. 2005 Jun 16;435(7044):959-63
15959515
Exp Parasitol. 1999 Jun;92(2):144-53
10366539
Eur J Immunol. 2003 Nov;33(11):2974-9
14579265
J Clin Invest. 2006 Nov;116(11):2914-23
17024245
Inflamm Bowel Dis. 2008 Jul;14(7):931-41
18300276
J Immunol. 2004 Jun 15;172(12):7635-41
15187144
J Exp Med. 1994 Jan 1;179(1):347-51
8270879
J Exp Med. 2006 Dec 25;203(13):2841-52
17145958
Science. 2004 May 21;304(5674):1154-8
15155948
Am J Physiol Lung Cell Mol Physiol. 2007 Aug;293(2):L305-13
17545488
Science. 2002 Mar 1;295(5560):1726-9
11872843
Infect Immun. 2005 Jan;73(1):385-94
15618176
Cell. 2004 Jul 23;118(2):229-41
15260992
J Parasitol. 1962 Jun;48:433-7
14008332
Eur J Immunol. 1994 Dec;24(12):3113-8
7805740
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):502-6
11209052