title: T cell developmental defects in 'viable motheaten' mice deficient in SHP-1 protein-tyrosine phosphatase. Developmental defects are corrected in vitro in the presence of normal hematopoietic-origin stromal cells and in vivo by exogenous IL-7.
abstract: Defects in the gene that encodes SHP-1 protein tyrosine phosphatase result in multiple hematopoietic abnormalities and generalized autoimmunity in viable motheaten (me(v)) mice. These mice also exhibit early thymic involution and abnormalities in T cell development. Here, we describe the use of fetal thymic organ culture (FTOC) and bone marrow adoptive transfer to study the effects of SHP-1 deficiency on thymocyte development. Chimeric FTOC established with normal bone marrow placed onto deoxyguanosine-treated fetal thymic lobes or onto scid fetal thymic lobes generated T cells. Bone marrow from SHP-1-deficient me(v)/ me(v) mice generated decreased numbers of T cells in chimeric FTOC established using deoxyguanosine-treated thymi but generated normal numbers in chimeric FTOC established using scid thymi. However, scid fetal thymi seeded with me(v)/ me(v) bone marrow also exhibited morphological abnormalities and contained elevated numbers of macrophages. Addition of IL-7 to me(v)/ me(v) bone marrow-seeded scid FTOC led to increased cell numbers, particularly of macrophages. Intrathymic injection of IL-7 partially restored the ability of progenitor cells in me(v)/ me(v) bone marrow to populate the thymus of adoptive recipients. We conclude that abnormal T cell development in me(v)/ me(v) mice may in part be due to defects in the ability of bone marrow-derived accessory cells to provide bioavailable IL-7 to developing thymocytes.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Sherri W
authors.initials: SW
authors.lastname: Christianson
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Dominick
authors.initials: D
authors.lastname: Deluca
authors.forename: Jean
authors.initials: J
authors.lastname: Leif
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Phillips
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Hayes
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Joliat
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Lyons
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation; D005333:Fetus / Q000166:cytology / Q000276:immunology; D015851:Interleukin-7 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D009924:Organ Culture Techniques; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics; D011828:Radiation Chimera; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D015851:Interleukin-7; D047908:Intracellular Signaling Peptides and Proteins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse