Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression.

Abstract

The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin {beta}7, but not for {beta}1 or {beta}2 integrins. Viable motheaten mice deficient for SHP-1 have less {beta}7 on T cells and lack {beta}7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in {beta}7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses {beta}7 endocytosis: internalization of {beta}7 but not {beta}1 integrin is accelerated in SHP-1+/- and CD22-/- B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce 4{beta}7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control {beta}7 expression. Integrin 4{beta}7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/- B cells display reduced {beta}7-dependent homing to gut associated Peyers patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin {beta}7-specific role for CD22-SHP-1 interplay in mucosal immunity.