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

TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, andproliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responsesagainst a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCRsignaling. STAP-2??deficient T cells showed reduced, whereas STAP-2??overexpressing T cells showed enhanced, TCR-mediated signalingand downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3fimmunoreceptor tyrosineactivation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2expression is required for full activation of downstream TCR signaling. Importantly, STAP-2??deficient mice exhibited slight phenotypesof CD4+T-cell??mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2??overexpressingtransgenic 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 thechimeric Ag receptor T cell therapy.The Journal of Immunology, 2022, 209: 57??68

Automated summary

This study identifies signal-transducing adaptor protein-2 (STAP-2) as a positive regulator of TCR signaling. STAP-2 deficiency leads to reduced TCR-mediated signaling and cytokine production, while STAP-2 overexpression enhances these responses. STAP-2 is associated with TCR signaling and is required for full activation of downstream TCR signaling. Manipulating STAP-2 may improve the treatment of patients with autoimmune diseases and chimeric Ag receptor T cell therapy.