ANTIGEN-RECEPTOR INDUCED CLONAL EXPANSION AND DELETION OF LYMPHOCYTESARE 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 antig en receptors on B and T lymphocytes, implicating involvement of this m olecule in the signal transduction pathways from the antigen receptors as a substrate of membrane-associated tyrosine kinase(s). The develop ment of lymphoid cells in HS1-deficient mice, generated through gene t argeting, appeared normal. However, antibody production to T-independe nt antigen and proliferative responses of splenic B and T cells after cross-linking of the antigen receptors were impaired in these mutant m ice. Furthermore, B cells in the peritoneal cavity of the mutant mice were resistant to multivalent cross-linking of the antigen receptor, w hich causes apoptosis of such cells in normal mice. Crossing the HS1-d eficient mice with the mice harboring transgenes encoding alpha and be ta chains of T-cell antigen receptor against a male H-Y antigen result ed 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 a nd plays important roles not only in clonal expansion, but also in clo nal deletion of B and T cells.