Tumor necrosis factor alpha and interleukin-1 alpha inhibit through different pathways interferon-gamma-induced antigen presentation, processing and MHC class II surface expression on astrocytes, but not on microglia

Abstract.

Astrocytes and microglia, two glial cell populations of the CNS, have been described to be involved in many immune processes. We used defined combinations of cytokines, interferon gamma (IFN-γ)/interleukin-1 alpha (IL-1α) and IFN-γ/tumor necrosis factor alpha (TNFα), to simulate different in vitro immune environments observed in disease or inflammation. In these conditions, we analyzed and compared the regulating effects of these cytokines on cell surface and total expression of MHC II and on the capacity of murine astrocytes and microglia to present peptide and native antigens to specific primed T cells. Neither IL-1α nor TNFα affected the IFN-γ-induced antigen presentation capacity of microglia. Astrocytes, however, were severely impaired in their capacity to present native antigens and, to a minor extent, a peptide antigen. Total expression of MHC II was not affected by these cytokines in microglia, whereas in astrocytes it was reduced by IL-1α and increased by TNFα. Both cytokines downregulated MHC II expression at the surface of astrocytes, but not of microglia. This shows that TNFα affects the of IFN-γ-immunocompetent astrocytes to process and present antigen, probably either by altering membrane traffic of MHC II and of antigen and/or enzymatic activities associated with these mechanisms, while IL-1α does so by downregulating MHC II expression. Altogether, our results illustrate how differently astrocytes and microglia react toward a defined, similar immune environment. One type of cell, the astrocytes, downregulate their T-cell stimulation and MHC II trafficking, and probably also their antigen processing, functions while the other, the microglia, maintain their antigen presentation potential.