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₄β₇/MAdCAM-1 Interactions Play an Essential Role in Transitioning Cryptopatches into Isolated Lymphoid Follicles and a Nonessential Role in Cryptopatch Formation¹

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

The ₄ integrins ₄β₇ and ₄β₁, and their ligands mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) and VCAM-1, have diverse functions, including roles in the formation of secondary lymphoid tissues at early time points during the colonization and clustering of the fetal lymphoid tissue inducer (LTi) cells and at later time points during the recruitment of lymphocytes. In this study, we evaluated the role of ₄ integrins in the development of a recently appreciated class of intestinal lymphoid tissues, isolated lymphoid follicles (ILFs). We observed that diverse ILF cellular populations express ₄β₇ and ₄β₁, including the LTi-like cells and lymphocytes, while ILF stromal cells and vessels within ILFs express VCAM-1 and MAdCAM-1, respectively. Evaluation of adult and neonatal β₇^–/– mice and adult and neonatal mice given blocking Abs to ₄β₇, MAdCAM-1, or VCAM-1 did not identify a role for ₄ integrins in cryptopatch (CP) development; however, these studies demonstrated that ₄β₇ and MAdCAM-1 are required for the transitioning of CP into lymphoid tissues containing lymphocytes or ILFs. Competitive bone marrow transfers demonstrated that β₇^–/– LTi-like cells had a reduced but not significantly impaired ability to localize to CP. Bone marrow transfers and adoptive transfers of B lymphocytes revealed that β₇ expression by B lymphocytes was essential for their entry into the developing ILFs. These findings demonstrate an essential role for ₄β₇/MAdCAM-1 in ILF development corresponding to the influx of β₇-expressing lymphocytes and a nonessential role for β₇-localizing LTi-like cells to the small intestine.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grant DK-64798 (to R.D.N.), the Crohn’s and Colitis Foundation of America (to C.W.), the Washington University School of Medicine Digestive Diseases Research Core Center Grant (P30-DK52574), and The Siteman Cancer Center High Speed Cell Sorting Core supported in part by a National Cancer Institute Cancer Center Support Grant (P30 CA91842).

² Address correspondence and reprint requests to Dr. Rodney D. Newberry, 660 South Euclid Avenue, Box 8124, St. Louis, MO 63110. E-mail address: rnewberry{at}im.wustl.edu

³ Abbreviations used in this paper: MAdCAM-1, mucosal addressin cell adhesion molecule 1; LTi, lymphoid tissue inducer; CP, cryptopatch; ILF, isolated lymphoid follicle; LT, lymphotoxin; LTβR, LT β receptor; PP, Peyer’s patch; HEV, high endothelial venule; PNAd, peripheral lymph node addressin.