STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals

Abstract TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens....

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Published in:The Journal of immunology (1950) 2022-07, Vol.209 (1), p.57-68
Main Authors: Saitoh, Kodai, Kashiwakura, Jun-ichi, Kagohashi, Kota, Sasaki, Yuto, Kawahara, Shoya, Sekine, Yuichi, Kitai, Yuichi, Muromoto, Ryuta, Ichii, Michiko, Nakatsukasa, Hiroko, Yoshimura, Akihiko, Oritani, Kenji, Matsuda, Tadashi
Format: Article
Language:English
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Summary:Abstract TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2–deficient T cells showed reduced, whereas STAP-2–overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2–deficient mice exhibited slight phenotypes of CD4+ T-cell–mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2–overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2101014