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

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Journal of Autoimmunity (Impact Factor: 8.41). 04/2002; 18(2):119-30. DOI: 10.1006/jaut.2001.0571
Source: PubMed


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.

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    • "In addition, our laboratory has demonstrated that SHP-1 is necessary for the normal differentiation and distribution of all glial subtypes within the murine CNS (Wishcamper et al., 2001). Although overwhelming evidence from the hematopoietic system indicates that SHP-1 is a negative regulator of cell signaling cascades (Mason et al., 1997; Berg et al., 1998; Kozlowski et al., 1998; Christianson et al., 2002; Joliat et al., 2002), its expression and function in the CNS are only now beginning to be elucidated. "
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    Scandinavian Journal of Immunology 06/2003; 57(5):410-22. DOI:10.1046/j.1365-3083.2003.01206.x · 1.74 Impact Factor
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    ABSTRACT: The role of the tyrosine phosphatase SHP-1 in the hematopoietic system has been well studied; however, its role in the central nervous system (CNS) response to injury is not well understood. Previous studies in our laboratory have demonstrated increased immunoreactivity for SHP-1 in a subset of reactive astrocytes that do not appear to enter the cell cycle following deafferentation of the chicken auditory brainstem. In order to determine whether mammalian astrocytes also upregulate SHP-1 immunoreactivity following CNS injury, a mouse model of focal cerebral ischemia was utilized to study SHP-1 expression. The brains of 3-week-old mice were analyzed at four time points following permanent middle cerebral artery occlusion (MCAO): 1, 3, 7, and 14 days. Our results demonstrate consistent infarct volumes within surgical groups, and infarct volumes decrease as a function of time from 1 day (maximum infarct volume) to 14 days (minimum infarct volume) post-MCAO. In addition, SHP-1 protein levels are upregulated following cerebral ischemia and this increase peaks at 7 days post-MCAO. Analysis of confocal images further reveals that immunoreactivity for SHP-1 occurs predominantly in GFAP+ reactive astrocytes, although a small percentage of F4-80+ microglia are also double labeled for SHP-1 at early times post-MCAO. These SHP-1+ reactive astrocytes do not appear to enter the cell cycle (as defined by PCNA immunoreactivity), confirming our previous studies in the avian auditory brainstem. These results suggest that SHP-1 plays an important role in the regulation of glial activation and proliferation in the ischemic CNS.
    Brain Research 07/2003; 974(1-2):88-98. DOI:10.1016/S0006-8993(03)02564-2 · 2.84 Impact Factor
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