Sh2d2a, encoding the T-cell specific adapter protein (TSAd), is crucial for T-cell activation regulation. It modulates signaling downstream of the T-cell receptor (TCR), and its expression is regulated at both transcriptional and translational levels [1,3]. cAMP signaling can prime T-cells for prompt TSAd protein expression upon TCR stimulation, and transcriptional activation of Sh2d2a depends on a cAMP-responsive element in the proximal promoter [3,7].

In Sh2d2a-deficient TCR-transgenic BALB/c mice, increased resistance to transplanted multiple myeloma development was observed, suggesting a modulatory role of Sh2d2a in T-cell mediated immune surveillance of cancer [1]. In addition, an SH2D2A loss-of-function frameshift mutation in tumor-infiltrating lymphocytes could activate T-cell effector functions in vitro [2]. Also, genetic studies on humans showed that the SH2D2A gene may contribute to the susceptibility of multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy, and juvenile rheumatoid arthritis [4,5,6,8].

In conclusion, Sh2d2a plays a significant role in regulating T-cell activation and has implications in cancer immune surveillance and autoimmune diseases. Mouse models, especially those with Sh2d2a deficiency, have been instrumental in uncovering its role in these biological processes and disease conditions, providing insights into potential therapeutic strategies for cancer immunotherapy and understanding the genetic susceptibility of autoimmune diseases.