Norin U, Rintisch C, Meng L, Forster F, Ekman D, Tuncel J, Klocke K, Bäcklund J, Yang M, Bonner MY, Lahore GF, James J, Shchetynsky K, Bergquist M, Gjertsson I, Hubner N, Bäckdahl L, Holmdahl R
Nat Commun 12 (1) 610 [2021-12-00; online 2021-01-27]
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.