Cellular and molecular characterization of the scurfy mouse mutant
| Autor: | L B, Clark, M W, Appleby, M E, Brunkow, J E, Wilkinson, S F, Ziegler, F, Ramsdell |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Immunoconjugates Lactams Macrocyclic T-Lymphocytes Receptors Antigen T-Cell Lymphocyte Activation Abatacept Mice Antigens CD Benzoquinones Animals CTLA-4 Antigen Mice Inbred C3H Quinones Granulocyte-Macrophage Colony-Stimulating Factor Nuclear Proteins Antigens Differentiation Genistein Lymphoproliferative Disorders Mice Mutant Strains Rifabutin B7-1 Antigen Cyclosporine Leukocyte Common Antigens Female Transcription Factors |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 162(5) |
| ISSN: | 0022-1767 |
| Popis: | Mice hemizygous (Xsf/Y) for the X-linked mutation scurfy (sf) develop a severe and rapidly fatal lymphoproliferative disease mediated by CD4+CD8- T lymphocytes. We have undertaken phenotypic and functional studies to more accurately identify the immunologic pathway(s) affected by this important mutation. Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfy T cells. Scurfy T cells also exhibit strong up-regulation of cell surface Ags indicative of in vivo activation, including CD69, CD25, CD80, and CD86. Both scurfy and normal T cells are responsive to two distinct signals provided by the TCR and by ligation of CD28; scurfy cells, however, are hyperresponsive to TCR ligation and exhibit a decreased requirement for costimulation through CD28 relative to normal controls. This hypersensitivity may result, in part, from increased costimulation through B7-1 and B7-2, whose expression is up-regulated on scurfy T cells. Although the specific defect leading to this hyperactivation has not been identified, we also demonstrate that scurfy T cells are less sensitive than normal controls to inhibitors of tyrosine kinases such as genistein and herbimycin A, and the immunosuppressant cyclosporin A. One interpretation of our data would suggest that the scurfy mutation results in a defect, which interferes with the normal down-regulation of T cell activation. |
| Databáze: | OpenAIRE |
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