Antigen-receptor induced clonal expansion and deletion of lymphocytes are impaired in mice lacking HS1 protein, a substrate of the antigen-receptor-coupled tyrosine kinases.
HS1, an intracellular protein expressed specifically in hematopoietic cells, is rapidly tyrosine phosphorylated after cross-linking of antigen receptors on B and T lymphocytes, implicating involvement of this molecule in the signal transduction pathways from the antigen receptors as a substrate of membrane-associated tyrosine kinase(s). The development of lymphoid cells in HS1-deficient mice, generated through gene targeting, appeared normal. However, antibody production to T-independent antigen and proliferative responses of splenic B and T cells after cross-linking of the antigen receptors were impaired in these mutant mice. Furthermore, B cells in the peritoneal cavity of the mutant mice were resistant to multivalent cross-linking of the antigen receptor, which causes apoptosis of such cells in normal mice. Crossing the HS1-deficient mice with the mice harboring transgenes encoding alpha and beta chains of T-cell antigen receptor against a male H-Y antigen resulted in a progeny that demonstrated a significantly impaired ability of thymic negative selection. These results indicate that HS1 is a novel molecule involved in the antigen-receptor-derived signaling pathways and plays important roles not only in clonal expansion, but also in clonal deletion of B and T cells.
Taniuchi
I
I
Department of Molecular Immunology, Kyushu University, Fukuoka, Japan.
Kitamura
D
D
Maekawa
Y
Y
Fukuda
T
T
Kishi
H
H
Watanabe
T
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000955:Antigens, T-Independent / Q000378:metabolism; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D001798:Blood Proteins / Q000502:physiology*; D002455:Cell Division; D017637:Clonal Deletion / Q000276:immunology*; D005362:Ficoll / Q000031:analogs & derivatives / Q000378:metabolism; D018390:Gene Targeting; D008221:Lymphoid Tissue / Q000254:growth & development / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010529:Peritoneal Cavity; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014301:Trinitrobenzenes / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000955:Antigens, T-Independent; D001798:Blood Proteins; C061909:HCLS1 protein, human; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; C020529:TNP-ficoll; D014301:Trinitrobenzenes; D005362:Ficoll; D011505:Protein-Tyrosine Kinases