Role of the gut-associated and secondary lymphoid tissue in the induction of chronic colitis.
BACKGROUND
It is well known that enteric bacterial antigens drive the development of chronic colitis in a variety of different mouse models of the inflammatory bowel diseases (IBD). The objective of this study was to evaluate the role of gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes (MLNs) and spleen in the pathogenesis of chronic colitis in mice.


METHODS
Surgical as well as genetic approaches were used to generate lymphopenic mice devoid of one or more of these lymphoid tissues. For the first series of studies, we subjected recombinase activating gene-1-deficient mice (RAG(-/-) ) to sham surgery (Sham), mesenteric lymphadenectomy (MLNx), splenectomy (Splx) or both (MLNx/Splx). In a second series of studies we intercrossed lymphotoxinβ-deficient (LTβ(-/-) ) mice with RAG(-/-) animals to generate LTβ(-/-) x RAG(-/-) offspring that were anticipated to contain functional MLNs but be devoid of GALT and most peripheral lymph nodes. Flow purified naïve (CD4(+) CD45RB(high) ) T-cells were adoptively transferred into the different groups of RAG(-/-) recipients to induce chronic colitis.


RESULTS
We found that at 3-5 wks following T-cell transfer, all four of the surgically-manipulated RAG(-/-) groups (Sham, MLNx, Splx and MLNx/Splx) developed chronic colitis that was similar in onset and severity. Flow cytometric analysis revealed no differences among the different groups with respect to surface expression of different gut-homing markers nor were there any differences noted in IFN-γ and IL-17 generation by mononuclear cells isolated among these surgically-manipulated mice. Although we anticipated that LTβ(-/-) x RAG(-/-) mice would contain functional MLNs but be devoid of GALT and peripheral lymph nodes (PLNs), we found that LTβ(-/-) x RAG(-/-) mice were in fact devoid of MLNs as well as GALT and PLNs. Adoptive transfer of CD45RB(high) T-cells into LTβ(-/-) x RAG(-/-) mice or their littermate controls (LTβ(+/+) x RAG(-/-) ) induced rapid and severe colitis in both groups.


CONCLUSIONS
Taken together, our data demonstrate that: a) neither the GALT, MLNs nor PLNs are required for induction of chronic gut inflammation in this model of IBD and b) T-and/or B-cells may be required for the development of MLNs in LTβ(-/-) mice.
Takebayashi
Koichi
K
Immunology and Inflammation Research Group LSU Health Sciences Center, Shreveport, Louisiana, USA.
Koboziev
Iurii
I
Ostanin
Dmitry V
DV
Gray
Laura
L
Karlsson
Fridrik
F
Robinson-Jackson
Sherry A
SA
Kosloski-Davidson
Melissa
M
Dooley
Angela Burrows
AB
Zhang
Songlin
S
Grisham
Matthew B
MB
D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology*; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D020381:Interleukin-17 / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue; D053308:Lymphotoxin-beta / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
D018398:Homeodomain Proteins; D020381:Interleukin-17; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta; C064658:RAG-1 protein
J Clin Invest. 2007 Mar;117(3):514-21
17332878
Springer Semin Immunopathol. 2005 Sep;27(2):167-80
15959782
J Exp Med. 2002 Jun 17;195(12):1613-24
12070288
Ann Intern Med. 2005 Dec 20;143(12):895-904
16365470
Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G135-46
19033538
Am J Pathol. 2002 Dec;161(6):2273-82
12466141
Curr Top Microbiol Immunol. 2006;308:59-82
16922086
Ann N Y Acad Sci. 2006 Aug;1072:187-93
17057199
Eur J Immunol. 2002 Apr;32(4):1109-13
11920578
Annu Rev Immunol. 2010;28:573-621
20192811
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9302-7
9256477
Cell. 2006 Feb 24;124(4):837-48
16497592
Immunol Rev. 2005 Aug;206:260-76
16048554
Ann N Y Acad Sci. 2004 Dec;1029:36-43
15681741
Nature. 2010 Mar 4;464(7285):59-65
20203603
Nat Rev Immunol. 2008 Jun;8(6):435-46
18500229
Nat Immunol. 2010 Jan;11(1):21-7
20016506
Gut. 2004 Mar;53(3):456-65
14960534
J Immunol. 2001 Sep 1;167(5):2781-90
11509623
J Immunol. 2007 Apr 15;178(8):4937-46
17404275
Nat Rev Immunol. 2003 Apr;3(4):331-41
12669023
Ann N Y Acad Sci. 2006 Aug;1072:218-32
17057202
Gastroenterology. 2009 Nov;137(5):1736-45
19632232
Am J Physiol Gastrointest Liver Physiol. 2006 Jan;290(1):G109-19
16099868
Trends Immunol. 2008 Nov;29(11):514-22
18838302
J Immunol. 2006 Jun 15;176(12):7533-41
16751400
Novartis Found Symp. 2003;252:92-8; discussion 98-105, 106-14
14609214
Gastroenterology. 2009 Jul;137(1):320-9
19233184
J Exp Med. 2006 Mar 20;203(3):497-500
16533891
Immunity. 1997 Apr;6(4):491-500
9133428
Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1706-14
17332469
J Exp Med. 2006 Mar 20;203(3):519-27
16533884
Infect Immun. 2008 Sep;76(9):4241-50
18625738