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

Abstract

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.

An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression

“…Intestinal HEV and PCV are also decorated by α2-6 sialic acid-capped glycotopes recognized by the B cell-specific lectin CD22 (Siglec2) 10 . These glycotopes constitute a B cell-specific mucosal vascular addressin, designated here BMAd, which selectively enhances the homing of B cells into GALT 10 , where they contribute to the IgA response to intestinal antigens and pathogens 11 . BMAd is synthesized by beta-galactoside alpha-2,6-sialyltransferase 1, encoded by St6gal1 , which like Madcam1 is selectively expressed by GALT HEV 10 .…”

Siglec Signaling in the Tumor Microenvironment

“…A recent study by Ballet et al. (2021) has further established Siglec-2 signaling on B cells induced by cis -ligands ( 186 ). Here, Siglec-2 was shown to associate with β 7 integrin in a sialic acid-dependent manner.…”

The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2–associated multisystem inflammatory syndrome in children

“…Moreover, in mice either expressing an active form of Notch1 in Tregs ( Foxp3 EGFPCre R26 N1c/+ ) or lacking NUMB expression in these cells ( Foxp3 EGFPCre Numb Δ/Δ ), treatment with polyinosinic:polycytidylic acid (poly I:C) to simulate viral infection induced systemic inflammation. Notch1 signaling in Tregs induced the B cell–inhibitory receptor CD22 ( 44 , 45 ), which promoted systemic inflammation in association with the expression of the α4β7 gut-homing receptor. CD22 destabilized Tregs and impaired their suppressive function in an mTORC1-dependent manner.…”

“…To delineate the mechanisms by which Notch1 signaling in Treg cells promotes multi organ inflammation in the context of a viral trigger, we analyzed the transcriptome of Notch1c-expressing Treg cells for pathways involved in the immune dysregulation(41). We found upregulation of CD22, a member of the Siglec family of lectins normally found in B cells, where it acts to regulate B cell receptor signaling(45).In particular, CD22 directs B cells to the intestinal lymphoid and mucosal tissues by upregulating the expression of the gut homing receptor a4b7(44). Flow cytometric analysis of Treg cells of Foxp3 EGFPCre R26 N1c/+ mice revealed increased CD22 expression upon treatment of the mice with Poly I:C (Fig.6A).…”