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

By Romain Ballet, Carolin Brandl, Ningguo Feng, Jeremy Berri, Julian Cheng, Borja Ocón, Amin Alborzian Deh Sheikh, Alex Marki, Clare L. Abram, Clifford A. Lowell, Takeshi Tsubata, Harry B Greenberg, Matthew S. Macauley, Klaus Ley, Lars Nitschke, Eugene C Butcher

Posted 02 Feb 2020
bioRxiv DOI: 10.1101/2020.01.31.929687

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 β7, but not for β1 or β2 integrins. Viable motheaten mice deficient for SHP-1 have less β7 on T cells and lack β7 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 β7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses β7 endocytosis: internalization of β7 but not β1 integrin is accelerated in SHP-1+/- and CD22-/- B cells. Moreover, mutations in CD22 cytoplasmic SHP-1-binding ITIM sequences reduce α4β7 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 β7 expression. Integrin α4β7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/- B cells display reduced β7-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 β7-specific role for CD22-SHP-1 interplay in mucosal immunity.

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