Interleukin-15 enhances proinflammatory T-cell responses in patients with MS and EAE
Cyril Laurent1, Gabrielle Deblois1, Marie-Laure Clénet1
1From the Department of Neurosciences (C. Laurent, G.D., M.-L.C., A.C.M., N.F.-k., M.G., P.D., A.P., C. Larochelle, N.A.), Université de Montréal and CRCHUM; and MS-CHUM Clinic (M.G., P.D., A.P., C. Larochelle), Québec, Canada.
Objective:
We posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model.
Methods:
We compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice.
Results:
IL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4+ and CD8+ T cells expressing CD122+, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration.
Conclusions:
Our results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.
Insights
Interleukin-15 (IL-15) amplifies T-cell inflammation in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Elevated IL-15 exacerbates disease severity and T-cell responses in both conditions.
Area of Science:
- Immunology
- Neuroscience
Background:
- Interleukin-15 (IL-15) is implicated in multiple sclerosis (MS) pathobiology due to elevated levels in patients.
- Investigating IL-15's role in T lymphocytes and the experimental autoimmune encephalomyelitis (EAE) mouse model is crucial.
Purpose of the Study:
- To determine the impact of IL-15 on T lymphocytes from MS patients.
- To elucidate the in vivo role of IL-15 in the EAE mouse model of MS.
Main Methods:
- Multiparametric flow cytometry and in vitro assays were used to compare T lymphocytes from MS patients and healthy controls (HCs).
- Peripheral IL-15 administration was tested in C57BL/6 mice after EAE disease onset.
Main Results:
- IL-15 enhanced STAT5 signaling and pro-inflammatory cytokine production (IFN-γ, GM-CSF, IL-17, TNF) in T cells from MS patients, with more robust effects on IL-17 and GM-CSF.
- In EAE mice, IL-15 administration aggravated clinical scores and increased inflammatory CNS-infiltrating T cells.
Conclusions:
- IL-15 significantly contributes to the amplification of T-cell inflammatory properties.
- These findings highlight IL-15 as a potential therapeutic target in MS and EAE.
