Impaired Immune Responses and Prolonged Allograft Survival in Sly1 Mutant Mice

Adaptiveimmunity is crucial for protective host defense and the development ofimmunological disorders. SLY1 was recently identified as anX-chromosomal SH3 protein that is serine phosphorylated (Ser27) uponB-and T-cell receptor engagement. Here, wedemonstrate that SLY1 is localized in the cytoplasm and the nucleus ofimmunocytes. We generated mice expressing a mutant version of SLY1lacking Ser27 and a functional nuclear localization signal. Thedefective SLY1 (SLY1d ) protein is localized exclusively inthe cytoplasm. B- and T-cell proliferation is attenuated and T-cellcytokine production is severely reduced.Sly1 d/d mice exhibit reduced lymphoid organ sizes, diminished marginal zoneB-cell numbers, and severely impaired antibody responses againstT-dependent and -independent antigens. Importantly, survival ofsemi-identical cardiac allografts was substantially prolonged inSly1 d/d mice. These results define SLY1 as anessential molecular component for the full activation of adaptiveimmunity.