Interleukin-15 and NKG2 receptors modulate CD8 T cell responses in the central nervous system during multiple sclerosis

Multiple sclerosis (MS) is a demyelinating inflammatory disease affecting the central nervous system (CNS). The pathology of MS is characterized by the infiltration of immune cells into the CNS as well as the activation of microglia and astrocytes. Oligodendrocytes are CNS-resident cells that are responsible for synthesizing and maintaining the myelin sheath around axons. They are considered to be the prime target cells in MS pathogenesis and their targeting by immune cells likely explains the loss of myelin that is characteristic of MS lesions.;First, we show that glial cells, especially astrocytes, expressed elevated levels of the pro-inflammatory cytokine interleukin (IL)-15 in MS lesions. Treatment of astrocytes in vitro with interferon-gamma (IFN-gamma), interleukin (IL)-1beta or tumor necrosis factor (TNF) resulted in elevated levels of IL-15. This IL-15 activated co-cultured antigen-specific CD8 T cell lines and augmented their lytic enzyme content. These functional enhancements led to increased cytotoxicity against target cells and were blocked by anti-IL-15 antibody. These results prove that IL-15 provided by astrocytes in MS lesions may enhance the effector function of CD8 T cells present in and around MS lesions and consequently exacerbate the observed tissue damage.;Second, we evaluated if oligodendrocytes express the ligands of NKG2D, which is an activating immune receptor expressed by CD8 T cells, gammadelta T cells and natural killer (NK) cells. IL-15 is known to increase NKG2D on these effector cells and to arm the NKG2D-mediated pathway of killing. We showed that oligodendrocytes in active MS lesions expressed elevated levels of NKG2D ligands. NKG2D ligands were expressed by primary human adult oligodendrocytes in vitro and increased their susceptibility to cytotoxicity mediated by all the NKG2D-expressing cells mentioned above. These results prove that oligodendrocytes in MS lesions may have an increased susceptibility to immune-mediated cytotoxicity because they express NKG2D ligands.;Third, we evaluated the contribution of human leukocyte antigen (HLA)-E to the dialogue between immune cells and oligodendrocytes. HLA-E can interact with NKG2A or NKG2C, which are expressed on CD8 T cells, gammadelta T cells and NK cells. Upon ligation to HLA-E, NKG2A inhibits the effector response whereas NKG2C augments it. We showed that primary human adult oligodendrocytes in vitro expressed HLA-E, and that this expression increased following treatment with IFN-gamma. HLA-E on oligodendrocytes conferred protection from NKG2A-expressing NK cells, and this protection was correlated with the levels of HLA-E. These results prove that oligodendrocytes express functional HLA-E molecules that can modulate the effector function of immune cells.;CD8 T cells constitute a prominent fraction of CNS-infiltrating immune cells. They have an effector memory phenotype and can persist as clonal expansions for years in the CNS of MS patients. This indicates that they are actively participating in the local immune response. The work presented in this thesis emanates from the hypothesis that the microenvironment of MS lesions favors and enhances the effector functions of CD8 T cells.;Our novel findings indicate that IL-15 may boost the effector functions of CD8 T cells and augment their propensity to kill oligodendrocytes that express NKG2D ligands. Both IL-15 and NKG2D ligands are involved in normal immune homeostasis, but both can exacerbate autoimmune responses if aberrantly expressed in targeted tissues. As we have shown that both are highly expressed in MS lesions, they might be implicated in the immune-mediated damage of CNS target cells characteristic of MS lesions. The increased expression of HLA-E on oligodendrocytes following treatment with IFN-gamma might protect them from immune-mediated cytotoxicity if the immune effectors express NKG2A. Further studies are required to elucidate if CNS-infiltrating CD8 T cells express NKG2A or NKG2C. This would determine if HLA-E represents an inhibitory or activating ligand for oligodendrocytes.