A CD22–Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity
Romain Ballet, Martin Brennan, Carolin Brandl, Ningguo Feng, Jeremy Berri, Julian Cheng, Borja Ocón, Amin Alborzian Deh Sheikh, Alex Márki, Yuhan Bi, Clare L. Abram, Clifford A. Lowell, Takeshi Tsubata, Harry B. Greenberg, Matthew S. Macauley, Klaus Ley, Lars Nitschke, Eugene C. Butcher
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. Lymphocyte homing to the gut and Peyer’s patches requires expression of integrin α4β7. Ballet and colleagues report that B cell expression of CD22 is required to specifically retain surface expression of β7 integrin molecules, thereby promoting B cell retention in the gut and optimal gut mucosal antibody responses.