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

Nat Immunol. 2021 Mar;22(3):381-390. doi: 10.1038/s41590-021-00862-z. Epub 2021 Feb 15.

Authors

Romain Ballet^{1

2}, Martin Brennan^#^{3

4}, Carolin Brandl^#⁵, Ningguo Feng^{3

6

7}, Jeremy Berri^{3

4}, Julian Cheng^{3

4}, Borja Ocón^{3

4}, Amin Alborzian Deh Sheikh⁸, Alex Marki⁹, Yuhan Bi^{3

4}, Clare L Abram¹⁰, Clifford A Lowell¹⁰, Takeshi Tsubata⁸, Harry B Greenberg^{3

6

7}, Matthew S Macauley^{11

12}, Klaus Ley⁹, Lars Nitschke⁵, Eugene C Butcher^{13

14}

Affiliations

¹ Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. ballet.r@gmail.com.
² Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ballet.r@gmail.com.
³ Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
⁴ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany.
⁶ Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
¹⁰ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
¹² Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
¹³ Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. ebutcher@stanford.edu.
¹⁴ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ebutcher@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Video-Audio Media

MeSH terms

Animals
B-Lymphocytes / enzymology*
B-Lymphocytes / immunology
B-Lymphocytes / virology
Chemotaxis, Leukocyte
Disease Models, Animal
Endocytosis
Female
Immunity, Mucosal*
Integrin beta Chains / immunology
Integrin beta Chains / metabolism*
Integrins / immunology
Integrins / metabolism*
Intestinal Mucosa / enzymology*
Intestinal Mucosa / immunology
Intestinal Mucosa / virology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / deficiency
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
Rotavirus / immunology
Rotavirus / pathogenicity
Rotavirus Infections / genetics
Rotavirus Infections / immunology
Rotavirus Infections / metabolism
Sialic Acid Binding Ig-like Lectin 2 / deficiency
Sialic Acid Binding Ig-like Lectin 2 / genetics
Sialic Acid Binding Ig-like Lectin 2 / metabolism*
Signal Transduction
Tissue Culture Techniques

Substances

Cd22 protein, mouse
Integrin beta Chains
Integrins
Sialic Acid Binding Ig-like Lectin 2
integrin alpha4beta7
integrin beta7
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Ptpn6 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding