Integrin activation mediates lymphocyte trafficking and immune functions. Conventional T cell (Tconv cell) integrin activation requires Rap1-interacting adaptor molecule (RIAM). Here, we report that Apbb1ip−/− (RIAM-null) mice are protected from spontaneous colitis due to IL-10 deficiency, a model of inflammatory bowel disease (IBD). Protection is ascribable to reduced accumulation and homing of Tconv cells in gut-associated lymphoid tissue (GALT). Surprisingly, there are abundant RIAM-null regulatory T cells (T reg cells) in the GALT. RIAM-null T reg cells exhibit normal homing to GALT and lymph nodes due to preserved activation of integrins αLβ2, α4β1, and α4β7. Similar to Tconv cells, T reg cell integrin activation and immune function require Rap1; however, lamellipodin (Raph1), a RIAM paralogue, compensates for RIAM deficiency. Thus, in contrast to Tconv cells, RIAM is dispensable for T reg cell integrin activation and suppressive function. In consequence, inhibition of RIAM can inhibit spontaneous Tconv cell–mediated autoimmune colitis while preserving T reg cell trafficking and function.
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October 26 2020
Distinct integrin activation pathways for effector and regulatory T cell trafficking and function
Hao Sun,
Hao Sun
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
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Frederic Lagarrigue,
Frederic Lagarrigue
Investigation, Methodology, Resources
1
Department of Medicine, University of California, San Diego, La Jolla, CA
2
Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
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Hsin Wang,
Hsin Wang
Investigation
1
Department of Medicine, University of California, San Diego, La Jolla, CA
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Zhichao Fan,
Zhichao Fan
Formal analysis, Investigation, Writing - review & editing
3
Department of Immunology, School of Medicine, UConn Health, Farmington, CT
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Miguel Alejandro Lopez-Ramirez,
Miguel Alejandro Lopez-Ramirez
Methodology, Resources, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
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John T. Chang,
John T. Chang
Investigation, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
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Mark H. Ginsberg
Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
Correspondence to Mark H. Ginsberg: mhginsberg@ucsd.edu
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Hao Sun
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
Frederic Lagarrigue
Investigation, Methodology, Resources
1
Department of Medicine, University of California, San Diego, La Jolla, CA
2
Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
Hsin Wang
Investigation
1
Department of Medicine, University of California, San Diego, La Jolla, CA
Zhichao Fan
Formal analysis, Investigation, Writing - review & editing
3
Department of Immunology, School of Medicine, UConn Health, Farmington, CT
Miguel Alejandro Lopez-Ramirez
Methodology, Resources, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
John T. Chang
Investigation, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
Mark H. Ginsberg
Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
1
Department of Medicine, University of California, San Diego, La Jolla, CA
Correspondence to Mark H. Ginsberg: mhginsberg@ucsd.edu
Received:
July 17 2020
Revision Received:
September 17 2020
Accepted:
September 22 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
American Heart Association
(18CDA34110228)
National Institutes of Health
(HL-129947, HL-151433, R01HL145454)
© 2020 Sun et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (2): e20201524.
Article history
Received:
July 17 2020
Revision Received:
September 17 2020
Accepted:
September 22 2020
Citation
Hao Sun, Frederic Lagarrigue, Hsin Wang, Zhichao Fan, Miguel Alejandro Lopez-Ramirez, John T. Chang, Mark H. Ginsberg; Distinct integrin activation pathways for effector and regulatory T cell trafficking and function. J Exp Med 1 February 2021; 218 (2): e20201524. doi: https://doi.org/10.1084/jem.20201524
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