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Isolated Lymphoid Follicles Lymphocytes Drive the Formation Of Adaptive Immune Responses Are Dispensable for Isolated Lymphoid Follicle Formation: Antigen-Naive, Lymphotoxin-Sufficient B Lymphocytes Drive the Formation of Mature This information is current as Isolated Lymphoid Follicles of September 24, 2021. Keely G. McDonald, Jacquelyn S. McDonough and Rodney D. Newberry J Immunol 2005; 174:5720-5728; ; doi: 10.4049/jimmunol.174.9.5720 Downloaded from http://www.jimmunol.org/content/174/9/5720 References This article cites 46 articles, 30 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/174/9/5720.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Adaptive Immune Responses Are Dispensable for Isolated Lymphoid Follicle Formation: Antigen-Naive, Lymphotoxin-Sufficient B Lymphocytes Drive the Formation of Mature Isolated Lymphoid Follicles1 Keely G. McDonald, Jacquelyn S. McDonough, and Rodney D. Newberry2 Isolated lymphoid follicles (ILFs) are recently appreciated members of the mucosal immune system. The architecture, composi- tion, and inducible nature of these structures indicates that these structures are tertiary lymphoid structures. The process leading to the formation of tertiary lymphoid structures, lymphoid neogenesis, has been observed in a number of inflammatory and autoimmune conditions. Given this association, there is considerable interest in identifying the factors promoting lymphoid Downloaded from neogenesis, and understanding the steps in this process. Using murine ILF formation as a model, we have examined the roles of different cellular sources of lymphotoxin (LT) and the adaptive immune response in lymphoid neogenesis. In this study, we report that, although other cellular sources of LT may supplant B lymphocytes in the formation of immature ILFs (loosely organized clusters of B lymphocytes), LT-sufficient B lymphocytes are required for the progression of immature ILFs to mature ILFs (organized lymphoid aggregates with a follicle-associated epithelium). ILF formation occurs in the absence of T lymphocytes and Ag-specific B lymphocyte responses, and ILF B lymphocytes express elevated levels of LT in the absence of antigenic stimulation. http://www.jimmunol.org/ Consistent with a role for chemokines inducing LT expression in Ag-naive B lymphocytes, and a chemokine-driven positive- feedback loop driving mature ILF formation, mature ILFs express elevated levels of B lymphocyte chemoattractant in the absence of Ag-specific B lymphocyte stimulation. These observations indicate that ILFs contain Ag-naive lymphocytes, and suggest that events occurring within ILFs shape subsequent immune responses mediated by these lymphocytes. The Journal of Immunology, 2005, 174: 5720–5728. he mucosal immune system is a complex network of lym- The initial identification of ILFs used B220ϩ staining of frozen phoid compartments working together to protect higher sections of murine intestine cut at an axis perpendicular to the villi, organisms from invading pathogens. The presence of ag- and did not allow assessment of the macroscopic architecture of by guest on September 24, 2021 T 3 ϩ gregates of mononuclear cells resembling Peyer’s patches (PP) or the B220 structures (4). Using whole-mount techniques and dis- lymph nodes in the human intestine is well documented (1–3); secting microscopy, we have identified a variety of structures con- however, the relationship of these structures to PP, the nature of taining B220ϩ cells, including loosely organized clusters of their formation, and their function has remained unclear. Analo- B220ϩ cells preferentially positioned at the base of villi, or im- gous structures, isolated lymphoid follicles (ILFs), have been iden- mature ILFs (iILFs), and well-organized lymphoid structures con- tified in the murine small intestine (4). ILFs were found to be taining a germinal center and an overlying FAE, or mature ILFs ϩ composed of predominantly B-2 B lymphocytes and CD4 T lym- (mILFs). The relationship of iILFs progressing to mILFs is sup- phocytes. And, like PP, ILF were found to possess a follicle-as- ported by several findings, which include the following: the iden- sociated epithelium (FAE) containing M cells (4). Recently, ILFs tical distribution and location of iILFs and mILFs; the require- were found to be sites for IgA class switching (5). ments for formation of iILFs are shared by mILFs, whereas not all of the requirements for formation of mILFs are shared by iILFs (indicating that iILFs precede mILFs); and the ability to promote Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110 the progression of iILFs to mILFs (6). Received for publication August 16, 2004. Accepted for publication February Several factors required for ILF formation have been identified. 24, 2005. These requirements parallel those required for PP and other sec- The costs of publication of this article were defrayed in part by the payment of page ondary lymphoid structure formation, but have key distinctions. charges. This article must therefore be hereby marked advertisement in accordance Like PP formation, ILF formation was found to be dependent on with 18 U.S.C. Section 1734 solely to indicate this fact. lymphotoxin (LT), LT␤R, and NF-␬␤-inducing kinase function 1 This work was supported in part by National Institutes of Health Grants DK064798 and ␤ DK060648, the Broad Medical Research Program IBD-0042, and Washington University because ILFs were absent in LT-deficient mice, LT R-deficient School of Medicine Digestive Diseases Research Core Center Grant P30-DK52574. mice, and aly/aly mice (4, 6). Although both ILF and PP formation 2 Address correspondence and reprint requests to Dr. Rodney D. Newberry, 660 South were found to be dependent on LT␤R-sufficient stromal cells, ILF Euclid Avenue, Box 8124, St. Louis, MO 63110. E-mail address: rnewberry@ and PP formation were found to differ in the cellular source of LT im.wustl.edu required for their formation. PP formation requires a LT-sufficient 3 Abbreviations used in this paper: PP, Peyer’s patch; FAE, follicle-associated epi- CD4ϩ, CD3Ϫ, bone marrow-derived cell, which may be a precur- thelium; ILF, isolated lymphoid follicle; iILF, immature ILF; mILF, mature ILF; LT, lymphotoxin; PNA, peanut lectin (agglutinin); HEL, hen egg white lysozyme; MH- sor to NK cells (7), whereas mILF formation was found to be CII, MHC class II; BLC, B lymphocyte chemoattractant; SLC, secondary lymphoid dependent on LT-sufficient B lymphocytes (6). tissue chemokine; ELC, EBV-induced molecule 1 ligand chemokine; SDF-1, stromal cell-derived factor-1; LTi, lymphoid tissue inducer; AID, activation-induced cytidine The requirement for LT-sufficient B lymphocytes is not only a deaminase. distinction between secondary lymphoid structure formation and Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 5721 ILF formation, but it also provides an opportunity for critical in- Whole mounts of small intestine sight into the process of ILF formation. LT expression is induced Small intestines were removed intact, flushed with cold PBS, and opened in B lymphocytes following activation, which occurs in the context along the mesenteric border. Intestines were mounted, lumen facing up and of BCR ligation by Ag. Alternatively, LT expression may be in- fixed with cold 10% phosphate-buffered formyl saline (Fisher Scientific) duced in Ag-naive B lymphocytes following chemokine receptor for1hat4°C. Intestines were washed three times in cold PBS, incubated ligation (8). Understanding the requirement for Ag exposure in ILF in a solution of 20 mM DTT, 150 mM Tris, and 20% ethanol at room temperature for 45 min, washed three times in cold PBS, and incubated in formation not only yields insight into the mechanisms leading to a solution of 1% H2O2 for 15 min at room temperature to block endogenous ILF formation, it also yields insight into the roles ILFs play in peroxidases. Intestines were washed three times in PBS, followed by in- immune responses. The requirement for previous Ag exposure cubation in PBS containing 1% BSA and 0.3% Triton X-100 for 30 min. would suggest that ILFs are less likely to be sites where immune Intestines were incubated with HRP-conjugated lectin from Ulex euro- paeus (UEA-I) (Sigma-Aldrich) in PBS, BSA, Triton X-100 solution over- responses to new Ags are shaped, and are more likely sites where night at 4°C to facilitate the identification of PP and mILF. The following Ag-experienced lymphocytes receive ongoing stimulation to per- day, intestines were washed three times in PBS, incubated in DAB metal petuate immune responses. The absence of a requirement for
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