A CD22-Shp1 phosphatase axis controls integrin β(7) 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 tissues (GALT). Here we describe unexpected involvement of tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec 2) in 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, B cells lacking CD22, or B cells 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.