A CD22–Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity

The integrin α 4 β 7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of α 4 β 7 surface expression and gut immunity. Shp1 selectively inhibited β 7 endocytosis, enhancing surface α 4 β 7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid–dependent manner with integrin β 7 on the cell surface to target intracellular Shp1 to β 7 . Shp1 restrained plasma membrane β 7 phosphorylation and inhibited β 7 endocytosis without affecting β 1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface α 4 β 7 and in homing to GALT. Consistent with the specialized role of α 4 β 7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses. Lymphocyte homing to the gut and Peyer’s patches requires expression of integrin α 4 β 7 . Ballet and colleagues report that B cell expression of CD22 is required to specifically retain surface expression of β 7 integrin molecules, thereby promoting B cell retention in the gut and optimal gut mucosal antibody responses.