Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β 7 integrin expression

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 β, but not for β or β integrins. mice deficient for SHP-1 have less β on T cells and lack β 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 β expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses β endocytosis: internalization of β but not β integrin is accelerated in SHP-1 and CD22 B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce αβ 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 β expression. Integrin αβ selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1 B cells display reduced β-dependent homing to gut associated Peyer’s 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 β-specific role for CD22-SHP-1 interplay in mucosal immunity.