Murine gammaherpesvirus 68 (␥HV-68; also referred to as MHV-68) is a gammaherpesvirus which infects murid rodents. Previous studies showed that CD8 T cells are important for controlling ␥HV-68 replication during the first 2 weeks of infection and suggested a role for B cells in latent or persistent ␥HV-68 infection. To further define the importance of B cells and CD8 T cells during acute and chronic ␥HV-68 infection, we examined splenic infection in mice with null mutations in the transmembrane domain of the-heavy-chain constant region (MuMT; B-cell and antibody deficient) or in the  2-microglobulin gene ( 2 ؊/؊ ; CD8 deficient). Immunocompetent mice infected intraperitoneally with ␥HV-68 demonstrated peak splenic titers 9 to 10 days postinfection, cleared infectious virus 15 to 20 days postinfection, and harbored low levels of latent virus at 6 weeks postinfection.  2 ؊/؊ mice showed peak splenic ␥HV-68 titers similar to those of normal mice but were unable to clear infectious virus completely from the spleen, demonstrating persistent infectious virus 6 weeks postinfection. These data indicate that CD8 T cells are important for clearing infectious ␥HV-68 from the spleen. Infected MuMT mice did not demonstrate detectable infectious ␥HV-68 in the spleen at any time after infection, indicating that mature B lymphocytes are necessary for acute splenic infection by ␥HV-68. Despite the lack of measurable acute infection, MuMT spleen cells harbored latent virus 6 weeks postinfection at a level about 100-fold higher than that in normal mice. These data demonstrate establishment of latency by a herpesvirus in an organ in the absence of acute viral replication in that organ. In addition, they demonstrate that ␥HV-68 can establish latency in a cell type other than mature B lymphocytes.
The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.
PTEN deficiency predisposes to a subset of human cancers, but the mechanism that underlies such selectivity is unknown. We have generated a mouse line that conditionally deletes Pten in urogenital epithelium. These mice develop carcinomas at high frequency in the prostate but at relatively low frequency in the bladder, despite early and complete penetrance of hyperplasia in both organs. Cell proliferation is initially high in the bladder of newborn Pten-deficient mice but within days is inhibited by p21 induction. In contrast, proliferation remains elevated in Pten-deficient prostate, where p21 is never induced, suggesting that p21 induction is a bladder-specific compensatory mechanism to inhibit proliferation caused by Pten deletion. Furthermore, the AKT/mammalian target of rapamycin growth pathway, which is highly activated in Ptendeficient prostate, is not activated in bladder epithelium. Our results reveal alternative downstream signaling pathways activated by Pten deficiency that lead to tissue-specific susceptibilities to tumorigenesis. (Cancer Res 2006; 66(4): 1929-39)
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