SumrrlaryA dominant gene carried in certain inbred mouse strains confers susceptibility to tumors induced by polyoma virus. This gene, designated Pyv s, was defined in crosses between the highly susceptible C3H/BiDa strain and the highly resistant but H-2k-identical C57BR/cdJ strain. The resistance of C57BR/cdJ mice is overcome by irradiation, indicating an immunological basis. In F1 x C57BR/cdJ backcross mice, tumor susceptibility cosegregates with Mtv-7, a mouse mammary tumor provirus carried by the C3H/BiDa strain. This suggests that Pyv s might encode the Mtv-7 superantigen (SAG) and abrogate polyoma tumor immunosurveillance through elimination of T cells bearing specific VB domains. DNA typing of 110 backcross mice showed no evidence of recombination between Pyv s and Mtv-7. Strongly biased usage of VB6 by polyoma virus-specific CD8 § cytotoxic T lymphocytes in C57BR/cdJ mice implicates T cells bearing this Mtv-7 SAG-reactive VB domain as critical anti-polyoma tumor effector cells in vivo. These results indicate identity between Pyv s and Mtv-7 sag, and demonstrate a novel mechanism of inherited susceptibility to virus-induced tumors based on effects of an endogenous superantigen on the host's T cell repertoire.

No abstract

Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3-10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1alpha and -beta [MIP-1alpha, MIP-1beta]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), MIP-1alpha, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-alpha) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system.

Th1/Th17 cells, secreting both IFNγ and IL-17, are often associated with inflammatory pathology. We cloned and studied the cytokine phenotypes of MBP-specific, TCR-identical encephalitogenic CD4+ cells in relationship to Th1-and Th17-associated transcription factors T-bet and RORγt. IFNγ-producing cells could be sub-divided into those that are T-bet + /RORγt − and those that are Tbet + /RORγt + . The latter comprises a spectrum of phenotypes, as defined by IL-17 production, and can be induced to up-regulate IL-23R with IL-12 or IL-23. The former, bona fide Th1 cells, lack IL-23R expression under all conditions. In vivo, T-bet + /RORγt − and T-bet + /RORγt + clones induce EAE equally well.

Stimulation of T cells by retroviral and bacterial super-antigens is followed by specific T cell elimination, in contrast with stimulation of T cells by peptide, which is usually associated with clonal expansion. We show here that this differential response phenotype is apparent at the level of individual T cell clones following TCR ligation with peptide or MTV antigen. We exploited selective coupling of apoptosis to TCR ligation by MTV7 to examine some of the intracellular biochemical events that underlie this response. MTV-dependent activation resulting in apoptosis was associated with activation of phospholipase A2 and the generation of reactive oxygen intermediates. Inhibition of these biochemical events prevented both MTV-dependent activation and apoptosis without affecting the peptide-dependent response of the same T cell clones. These results indicate that clonal expansion or programmed cell death following TCR ligation may be consequences of distinct TCR-coupled signaling pathways.