Interleukin-15 amplifies the pathogenic activity of CD4(+) CD28-T cells in multiple sclerosis patients

Abstract

Purpose/Objective: Immune ageing or immunosenescence, contributes to the increased morbidity and mortality seen in the elderly. Premature immunosenescence is shown to occur in patients with multiple sclerosis(MS). The main characteristic of immunosenescence is the expansion of CD4+ CD28- T cells in the peripheral blood. We showed that these cells accumulate in brain lesions of MS patients CD24+ CD28- T cells have a cytotoxic profile, shown by expression of the cytotoxic molecules perforin, granzyme B and NKG2D, an activating natural killer (NK) cell receptor. For NK cells, it is known that NKG2D expression and cytotoxicity increase in response to interleukin (IL)-15, which is upregulated in the serum and cerebrospinal fluid of MS patients. The aim of our study is to investigate whether IL-15 enhances cytotoxicity of CD4+ CD28- T cells as seen for NK cells. Materials and methods: Flow cytometric analysis was used to investigate proliferation, expression of cytotoxic molecules and degranulation of CD4+ CD28- T cells in response to IL-15. Coculture with the NKG2D ligand expressing cell line U251 assessed the contribution of NKG2D ligation to degranulation of CD4+ CD28- T cells. To identify IL-15 producing cells in the brain, immunohistochemistry was performed on MS lesion tissue and normal brain tissue of non-demented controls. Results: We show that IL-15 preferentially induces proliferation of CD4+ CD28- T cells as compared to their CD28+ counterparts. Phenotypically, IL-15 significantly increases expression of NKG2D perforin and granzyme B by CD4+ CD28- T cells. Also, the production of interferon-gamma is increased, and this increase is significantly higher in MS patients. When IL-15 is presented to CD4+ CD28- T cells, their release of cytotoxic granules is significantly enhanced. This degranulation is not dependent on NKG2D ligation, bu blocking of NKG2D diminished this process. In MS lesions, we found that microglia/macrophages are the main IL-15 producing cells and that CD4+ T cells are found in close proximity to them, suggesting in vivo stimulation. Conclusions: In summary, our findings indicate that CD4+ CD28- T cells, which accumulate in brain lesions of MS patients, are functionally boosted by IL-15 producing cells. This process amplifies their cytotoxicity, contributing to local damage.