Distinct but overlapping epitopes are involved in α₄β₇-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation

The mouse CD8⁺ T cell lymphoma TK1 expresses high levels of α₄β₇ integrin, which it can use to interact with multiple ligands including mucosal addressin-1 (MAdCAM-1), VCAM-1, and fibronectin. In addition, α₄β₇ can support TK1 cell aggregation. Here we have produced and characterized a panel of mAbs against α₄β₇ to define antigenic and functional epitopes associated with its distinct functions. One mAb, DATK32, is unique in recognizing an epitope specific to the α₄β₇ heterodimer. Furthermore, DATK32 induces TK1 cell aggregation yet inhibits TK1 cell adhesion to MAdCAM-1, VCAM-1, and fibronectin. Considered as a whole, the panel of anti-α₄β₇ mAbs studied define unique patterns of inhibition for α₄β₇ binding to each of its defined molecular ligands. We conclude that α₄β₇ interactions with MAdCAM-1, VCAM-1, and fibronectin can be modulated by Ab binding to distinct epitopes and thus probably involve functionally separable, although physically overlapping binding sites on this multifunctional integrin. These findings are consistent with the general observation that integrins use distinct, potentially differentially regulated interaction sites for adhesion to multiple ligands. Extension of these concepts to α₄β₇ has important considerations for understanding the roles of this integrin in lymphocyte homing to mucosal sites and in cell-cell interactions during the immune response.