α₄β₇/MAdCAM-1 interactions play an essential role in transitioning cryptopatches into isolated lymphoid follicles and a nonessential role in cryptopatch formation

The α₄ integrins α₄β₇ and α₄β₁, 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 α₄ 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 α₄β₇ and α₄β₁, 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 α₄β₇, MAdCAM-1, or VCAM-1 did not identify a role for α₄ integrins in cryptopatch (CP) development; however, these studies demonstrated that α₄β₇ 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 α₄β ₇/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.