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

Abstract

The integrin α₄β₇ 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 α₄β₇ surface expression and gut immunity. Shp1 selectively inhibited β₇ endocytosis, enhancing surface α₄β₇ display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin β₇ on the cell surface to target intracellular Shp1 to β₇. Shp1 restrained plasma membrane β₇ phosphorylation and inhibited β₇ endocytosis without affecting β₁ 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 α₄β₇ and in homing to GALT. Consistent with the specialized role of α₄β₇ in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.