B Cell-Derived IL-15 Enhances CD8 T Cell Cytotoxicity and Is Increased in Multiple Sclerosis Patients

Abstract

Multiple lines of evidence suggest that CD8 T cells contribute to the pathogenesis of multiple sclerosis (MS). However, the sources and involvement of cytokines such as IL-15 in activating these cells is still unresolved. To investigate the role of IL-15 in enhancing the activation of CD8 T cells in the context of MS, we determined cell types expressing the bioactive surface IL-15 in the peripheral blood of patients and evaluated the impact of this cytokine on CD8 T cell cytotoxicity and migration. Flow cytometric analysis showed a significantly greater proportion of B cells and monocytes from MS patients expressing IL-15 relative to controls. We established that CD40L activation of B cells from healthy donors increased their IL-15 levels, reaching those of MS patients. We also demonstrated an enhanced cytotoxic profile in CD8 T cells from MS patients upon stimulation with IL-15. Furthermore, we showed that IL-15 expressed by B cells and monocytes is sufficient and functional, enhancing granzyme B production by CD8 T cells upon coculture. Exposure of CD8 T cells to this cytokine enhanced their ability to kill glial cells as well as to migrate across an in vitro inflamed human blood–brain barrier. The elevated levels of IL-15 in patients relative to controls, the greater susceptibility of CD8 T cells from patients to IL-15, in addition to the enhanced cytotoxic responses by IL-15–exposed CD8 T cells, stresses the potential of therapeutic strategies to reduce peripheral sources of IL-15 in MS.

IL-15 Amplifies the Pathogenic Properties of CD4+CD28− T Cells in Multiple Sclerosis

“…This effect was previously described for CD8 + T cells and NK cells (24,52). In our study, expression of NKG2D, perforin, granzyme B, and IFN-g were increased, as well as the frequency of degranulating cells.…”

“…In MS patients, both soluble and membrane-bound IL-15 levels are increased in the serum and cerebrospinal fluid (29)(30)(31). Recently, increased IL-15 expression was found on peripheral B cells and on astrocytes within brain lesions of MS patients, compared with control subjects (24,32). The cytotoxicity-enhancing effect of IL-15 has already been described for NK cells and CD8 + T cells (24,(32)(33)(34).…”

“…Recently, increased IL-15 expression was found on peripheral B cells and on astrocytes within brain lesions of MS patients, compared with control subjects (24,32). The cytotoxicity-enhancing effect of IL-15 has already been described for NK cells and CD8 + T cells (24,(32)(33)(34). Specifically, it was shown that the signaling pathways of IL-15 and the activating NK cell receptor NKG2D are intertwined (35).…”

IL-15-secreting γδT cells induce memory T cells in experimental allergic encephalomyelitis (EAE) mice

“…Two recent studies have shown that B cell-derived IL-15 (Schneider et al, 2011) and astrocyte-derived IL-15 enhance CD8 + T cell cytotoxicity in MS patients (Saikali et al, 2010). Except for ␥␦T1 and ␥␦T17 cells, it is unclear whether ␥␦T cells secrete …”

Journal Club: Intrathecal effects of daclizumab treatment of multiple sclerosis

“…P40 is a subunit of IL-12 and IL-23 and although less well studied, the p40 monomer as well as the p40 2 homodimer have been identified. 3 Importantly, IL-12 and IL-23 are thought to play central roles in CD4 T cell polarization and phenotypic plasticity favoring either a Th1 or a Th17 response. 10 Despite 10-fold concentration of CSF, measurements of most soluble mediators (13/16 tested) including IL-12 and IL-23 were below the detection limit of the assays used, suggesting that such CSF monitoring is not helpful as a measure of treatment efficacy.…”