Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation

Ulrika Norin (), Carola Rintisch, Liesu Meng, Florian Forster, Diana Ekman, Jonatan Tuncel, Katrin Klocke, Johan Bäcklund, Min Yang, Michael Y. Bonner, Gonzalo Fernandez Lahore, Jaime James, Klementy Shchetynsky, Maria Bergquist, Inger Gjertsson, Norbert Hubner, Liselotte Bäckdahl and Rikard Holmdahl ()
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Ulrika Norin: Karolinska Institute
Carola Rintisch: Karolinska Institute
Liesu Meng: Karolinska Institute
Florian Forster: Karolinska Institute
Diana Ekman: Karolinska Institute
Jonatan Tuncel: Karolinska Institute
Katrin Klocke: Karolinska Institute
Johan Bäcklund: Karolinska Institute
Min Yang: Karolinska Institute
Michael Y. Bonner: Karolinska Institute
Gonzalo Fernandez Lahore: Karolinska Institute
Jaime James: Karolinska Institute
Klementy Shchetynsky: Karolinska Institute and Karolinska University Hospital
Maria Bergquist: University of Gothenburg
Inger Gjertsson: University of Gothenburg
Norbert Hubner: Max-Delbrück-Center for Molecular Medicine (MDC)
Liselotte Bäckdahl: Karolinska Institute
Rikard Holmdahl: Karolinska Institute

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.

Date: 2021
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DOI: 10.1038/s41467-020-20586-2

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