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

Ballet, R.; Brandl, C.; Feng, N.; Berri, J.; Cheng, J.; Ocon, B.; Alborzian Deh Sheikh, A.; Marki, A.; Abram, C. L.; Lowell, C. A.; Tsubata, T.; Greenberg, H. B.; Macauley, M. S.; Ley, K.; Nitschke, L.; Butcher, E.

doi:10.1101/2020.01.31.929687

bioRxiv · 10.1101/2020.01.31.929687

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

Ballet, R.·Brandl, C.·Feng, N.·Berri, J.·Cheng, J.·Ocon, B.·Alborzian Deh Sheikh, A.·Marki, A.·Abram, C. L.·Lowell, C. A.·Tsubata, T.·Greenberg, H. B.·Macauley, M. S.·Ley, K.·Nitschke, L.·Butcher, E.

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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.

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Ballet, R., Brandl, C., Feng, N., Berri, J., Cheng, J., Ocon, B., Alborzian Deh Sheikh, A., Marki, A., Abram, C. L., Lowell, C. A., Tsubata, T., Greenberg, H. B., Macauley, M. S., Ley, K., Nitschke, L., Butcher, E.. 2020-02-02. Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression.. https://doi.org/10.1101/2020.01.31.929687

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