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

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

doi:10.1038/s41590-021-00862-z

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

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

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The integrin α₄β₇ 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 α₄β₇ surface expression and gut immunity. Shp1 selectively inhibited β₇ endocytosis, enhancing surface α₄β₇ display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid–dependent manner with integrin β₇ on the cell surface to target intracellular Shp1 to β₇. Shp1 restrained plasma membrane β₇ phosphorylation and inhibited β₇ endocytosis without affecting β₁ 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 α₄β₇ and in homing to GALT. Consistent with the specialized role of α₄β₇ in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.

Original language	English (US)
Pages (from-to)	381-390
Number of pages	10
Journal	Nature Immunology
Volume	22
Issue number	3
DOIs	https://doi.org/10.1038/s41590-021-00862-z
State	Published - Mar 2021
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Ballet, R., Brennan, M., Brandl, C., Feng, N., Berri, J., Cheng, J., Ocón, B., Alborzian Deh Sheikh, A., Marki, A., Bi, Y., Abram, C. L., Lowell, C. A., Tsubata, T., Greenberg, H. B., Macauley, M. S., Ley, K., Nitschke, L., & Butcher, E. C. (2021). A CD22–Shp1 phosphatase axis controls integrin β₇ display and B cell function in mucosal immunity. Nature Immunology, 22(3), 381-390. https://doi.org/10.1038/s41590-021-00862-z

Ballet, R, Brennan, M, Brandl, C, Feng, N, Berri, J, Cheng, J, Ocón, B, Alborzian Deh Sheikh, A, Marki, A, Bi, Y, Abram, CL, Lowell, CA, Tsubata, T, Greenberg, HB, Macauley, MS, Ley, K, Nitschke, L & Butcher, EC 2021, 'A CD22–Shp1 phosphatase axis controls integrin β₇ display and B cell function in mucosal immunity', Nature Immunology, vol. 22, no. 3, pp. 381-390. https://doi.org/10.1038/s41590-021-00862-z

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

abstract = "The integrin α4β7 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 α4β7 surface expression and gut immunity. Shp1 selectively inhibited β7 endocytosis, enhancing surface α4β7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid–dependent manner with integrin β7 on the cell surface to target intracellular Shp1 to β7. Shp1 restrained plasma membrane β7 phosphorylation and inhibited β7 endocytosis without affecting β1 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 α4β7 and in homing to GALT. Consistent with the specialized role of α4β7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.",

author = "Romain Ballet and Martin Brennan and Carolin Brandl and Ningguo Feng and Jeremy Berri and Julian Cheng and Borja Oc{\'o}n and {Alborzian Deh Sheikh}, Amin and Alex Marki and Yuhan Bi and Abram, {Clare L.} and Lowell, {Clifford A.} and Takeshi Tsubata and Greenberg, {Harry B.} and Macauley, {Matthew S.} and Klaus Ley and Lars Nitschke and Butcher, {Eugene C.}",

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doi = "10.1038/s41590-021-00862-z",

language = "English (US)",

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AU - Cheng, Julian

AU - Ocón, Borja

AU - Alborzian Deh Sheikh, Amin

AU - Marki, Alex

AU - Bi, Yuhan

AU - Abram, Clare L.

AU - Lowell, Clifford A.

AU - Tsubata, Takeshi

AU - Greenberg, Harry B.

AU - Macauley, Matthew S.

AU - Ley, Klaus

AU - Nitschke, Lars

AU - Butcher, Eugene C.

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AB - The integrin α4β7 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 α4β7 surface expression and gut immunity. Shp1 selectively inhibited β7 endocytosis, enhancing surface α4β7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid–dependent manner with integrin β7 on the cell surface to target intracellular Shp1 to β7. Shp1 restrained plasma membrane β7 phosphorylation and inhibited β7 endocytosis without affecting β1 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 α4β7 and in homing to GALT. Consistent with the specialized role of α4β7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.

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

Abstract

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