Integrins of the ␤7 subfamily, ␣4␤7 and ␣E␤7, contribute to lymphocyte homing and to the development of protective or autoreactive immune responses at mucosal sites. The ␤ subunits of integrins are considered important for regulation of stimulated cell adhesion and adhesion-dependent signal transduction. Using a yeast interaction trap screen, a human WD repeat protein, termed WAIT-1, was isolated that interacts with the integrin ␤7 cytoplasmic tail and is homologous to mouse EED and Drosophila ESC proteins. WAIT-1 also binds to the cytoplasmic domains of ␣4 and ␣E but not to those of integrin ␤1, ␤2, and ␣L subunits. Association of WAIT-1 and ␤7-integrin was confirmed by coprecipitation from transiently transfected 293 cells. The binding site for WAIT-1 was mapped to a short membrane-proximal region of the ␤7 cytoplasmic tail with Tyr-735 being of critical importance. Northern blot analysis revealed multiple WAIT-1-related transcripts with differential expression in circulating leukocytes, tissue-resident cells of diverse origin, and lymphoid malignancies. These results suggest that WAIT-1, together with the recently identified RACK1, may define a novel subfamily of WD repeat proteins that interact with distinct subsets of integrin cytoplasmic tails and may act as specific regulators of integrin function.Expression of ␤7-integrins, ␣4␤7 and ␣E␤7, is largely confined to leukocytes. Although ␣4␤7-integrin is homogeneously expressed on natural killer cells, eosinophils, and naive T and B cells, its distribution on effector/memory T and B cells is restricted to a subset of gut-homing lymphocytes (1-6). Peripheral blood monocytes do not express ␤7-integrins, but ␣4␤7 and ␣E␤7 are up-regulated upon stimulation of macrophage differentiation with phorbol ester or interferon-␥ (7). Recent studies have indicated that, in addition, ␣4␤7-integrin is induced on endothelial cells after treatment with proinflammatory mediators such as tumor necrosis factor (8). In contrast to ␣4␤7, expression of the ␣E␤7-integrin is confined to a subset of gutassociated T lymphocytes and dendritic cells (4,6,9).␤7-Integrins are considered important for the development and function of gut-associated lymphoid tissues. Interaction of ␣4␤7 with MAdCAM-1 allows for tissue-specific migration of circulating lymphocytes into the lamina propria and Peyer's patches of the gut (10, 11), whereas ␣E␤7 may retain intraepithelial lymphocytes within the gut epithelium through binding of E-cadherin on epithelial cells (12,13). Lack of ␤7-integrins severely impairs the development of the gut immune system, as Peyer's patches are absent or hypoplastic, and fewer intraepithelial lymphocytes are detected in ␤7-integrin-deficient mice (14). Moreover, gut-homing ␣4␤7 ϩ CD4 T cells specifically harbor cellular memory for intestinal antigens, suggesting that ␣4␤7 helps to target and segregate intestinal versus systemic immune responses (15).Integrins of the ␤7 family are involved in the development and/or progression of diseases such as colitis (16,17), diabetic insul...