PRESENTATION OF PROTEOLIPID PROTEIN EPITOPES AND B7-1-DEPENDENT ACTIVATION OF ENCEPHALITOGENIC T-CELLS BY IFN-GAMMA-ACTIVATED SJL J ASTROCYTES/

There is controversy regarding the possible role of glial cells as APC s in the pathogenesis of central nervous system (CNS) demyelinating di seases such as multiple sclerosis and its animal model, experimental a utoimmune encephalomyelitis (EAE), Microglia have been clearly shown t o present Ag in the CNS, and due to the proximity of activated astrogl ial cells to infiltrating T cells and macrophages in demyelinating les ions, it is also possible that astrocytes positively or negatively reg ulate disease initiation and/or progression. We examined the capacity of IFN-gamma-treated astrocytes from EAE-susceptible SJL/J mice to pro cess and present myelin epitopes. IFN-gamma activation up-regulated IC AM-1, VCAM-1, MHC class II, invariant chain, H2-M, CD40, and B7-1 as d etermined hy FAGS and/or RT-PCR analyses. B7-2 expression was only mar ginally enhanced on SJL/J astrocytes, Consistent with the expression o f these accessory molecules, IFN-gamma-treated SJL/J astrocytes induce d the B7-1-dependent activation of Th1 lines and lymph node T cells sp ecific for the immunodominant encephalitogenic proteolipid protein (PL P) epitope (PLP139w-151) as assessed by proliferation and activation f or the adoptive transfer of EAE. Interestingly, IFN-gamma-activated as trocytes efficiently processed and presented PLP139-151, but not the s ubdominant PLP178-191, PLP56-70 or PLP104-117 epitopes, from intact PL P and a recombinant variant fusion protein of PLP (MP4), The data are consistent with the hypothesis that astrocytes in the proinflammatory CNS environment have the capability of activating CNS-infiltrating enc ephalitogenic T cells specific for immunodominant epitopes on various myelin proteins that may be involved in either the initial or the rela psing stages of EAE.