Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.
Adaptive immunity is crucial for protective host defense and the development of immunological disorders. SLY1 was recently identified as an X-chromosomal SH3 protein that is serine phosphorylated (Ser27) upon B-and T-cell receptor engagement. Here, we demonstrate that SLY1 is localized in the cytoplasm and the nucleus of immunocytes. We generated mice expressing a mutant version of SLY1 lacking Ser27 and a functional nuclear localization signal. The defective SLY1 (SLY1(d)) protein is localized exclusively in the cytoplasm. B- and T-cell proliferation is attenuated and T-cell cytokine production is severely reduced. Sly1(d/d) mice exhibit reduced lymphoid organ sizes, diminished marginal zone B-cell numbers, and severely impaired antibody responses against T-dependent and -independent antigens. Importantly, survival of semi-identical cardiac allografts was substantially prolonged in Sly1(d/d) mice. These results define SLY1 as an essential molecular component for the full activation of adaptive immunity.
Beer
Sandra
S
Department of Surgery, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.
Scheikl
Tanja
T
Reis
Bernhard
B
Hüser
Norbert
N
Pfeffer
Klaus
K
Holzmann
Bernhard
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012694:Serine / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014184:Transplantation, Homologous
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D019913:Nuclear Localization Signals; D011948:Receptors, Antigen, T-Cell; C506091:SLY1 protein, mouse; D012694:Serine