The immunological disorder caused by the murine retrovirus LP-BM-5, termed MAIDS, is a useful animal model for studies of the acquired immunodeficiency syndrome (AIDS). Infection by the lP-BM5 retrovirus, like HIV in humans, causes early signs of B-cell activation including lymphadenopathy and hypergammaglobulinemia followed by a severe T-cell immunodeficiency and impaired resistance to bacterial pathogens. Progression of this disease is associated with chronic T-cell activation, leading to expression of TH2-type cytokines and B-cell expansion. We have recently found that elevated in vivo expression of Eta-1 (IL- 15), a recently-defined TH2-type cytokine discovered in our laboratory, is associated with the progression of MAIDS. By contrast, in vivo expression of other T-cell cytokines, with the possible exception of IL-10, is not detectably increased. Eta-1 (IL-15) interacts with receptors on macrophages and B-cells to provoke both IgM and IgG responses. The interaction between Eta-1 (IL-15) and receptors on macrophages also can inhibit the response to certain intracellular bacterial pathogens. We will test the hypothesis that dysregulated expression of Eta-1 (IL-15) is responsible for chronic in vivo activation of B-cells as well as impaired resistance to bacterial pathogens in experiments that examine the effects of altered expression of the Eta-1 gene on development of MAIDS. A second aspect of the proposed research project comes from our recent demonstration that TCR ligation by MTV superantigen is coupled to an alternative signalling pathway distinct from that induced by conventional peptide ligands and which results in selective expression of Eta-1 and T- cell unresponsiveness. Recent studies of MAIDS have indicated that chronic T-cell activation may reflect chronic stimulation by the superantigen-like gag60 protein of lP-BM5-infected B-cells, leading to T-cell anergy. We will test the hypothesis that T-cell activation by a superantigen associated with LP-BM5 infection results in selective expression of Eta-1 followed by unresponsiveness, as is the case for the murine retroviral superantigen M-MTV.
| Weber, G F; Abromson-Leeman, S; Cantor, H (1995) A signaling pathway coupled to T cell receptor ligation by MMTV superantigen leading to transient activation and programmed cell death. Immunity 2:363-72 |
