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Updated: Jun 7, 2025
Isolation and Th17 Differentiation of Naïve CD4 T Lymphocytes
Published on: September 26, 2013
Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple
Joana Hygino1, Marisa C Sales2, Priscila M Sacramento1
1Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.
Purpose:
The presence of T cells expressing TLR-2 and TLR-4 has been associated with relapsing-remitting multiple sclerosis (RRMS) pathogenesis. Here, we evaluated whether the effectiveness of DMT in controlling clinical activity of the disease would be associated with modulation of proportion of TLRs+ T cells.
Patients And Methods:
Whole peripheral blood mononuclear cells, purified CD4+ and CD8+ T cells from RRMS patients were cultured with different stimuli. The frequency of IL-17-secreting CD4+ and CD8+ T cells positive for TLR-2 and TLR-4 was determined by flow cytometry. The cytokine profile of these T cells following TLR-2 and TLR-4 stimulation was determined by Multiplex. Some of these T cell cultures were treated with hydrocortisone. The levels of LPS-binding protein (LBP) were dosed by ELISA. Clinical (occurrence of relapses) and radiological (number of active brain lesions) activity were evaluated during the 1-year follow-up.
Results:
Despite DMT, high intensity of TLR-2 and TLR-4 expression on (CD4+ and CD8+) T-cells, as well as the frequency of IL-17-secreting (CD4+ and CD8+) T-cells, are predictive of future RRMS relapses. Moreover, higher cytokine production related to Th17/Tc-17 phenotypes in response to TLR-2 and TLR-4 agonists was observed in DMT-treated patients and displayed an elevated number of brain lesions. The hyperresponsiveness of MS-derived T-cells to TLR-2 and TLR-4 ligands, with high levels of IL-1β, IL-6, IL-17, IFN-γ and GM-CSF in response to both TLR agonists, positively correlated with plasma LBP levels. Interestingly, corticoid was less efficient in reducing Th17 and Tc-17 cytokine production induced by TLR-2 and TLR-4 ligands in DMT-treated patients who relapsed during follow-up.
Conclusion:
Collectively, the data suggested that persistence of circulating Th17 and Tc17 cells expressing elevated levels of functional TLR-2 and TLR-4 could indicate high disease activity and lower therapeutic efficacy in RRMS patients.
Insights
High levels of Toll-like receptors (TLRs) on T cells predict relapsing-remitting multiple sclerosis (RRMS) relapses despite disease-modifying therapy (DMT). Persistent TLR-expressing T cells indicate high RRMS activity and reduced treatment effectiveness.
Area of Science:
- Immunology
- Neuroscience
- Pathogenesis of Multiple Sclerosis
Background:
- Toll-like receptors (TLRs) 2 and 4 on T cells are implicated in relapsing-remitting multiple sclerosis (RRMS) pathogenesis.
- Disease-modifying therapies (DMTs) aim to control RRMS clinical activity.
Purpose of the Study:
- To investigate if DMT effectiveness in controlling RRMS clinical activity correlates with changes in the proportion of T cells expressing TLR-2 and TLR-4.
- To assess the predictive value of TLR-expressing T cells for future disease activity in RRMS patients undergoing DMT.
Main Methods:
- Peripheral blood mononuclear cells and purified CD4+ and CD8+ T cells from RRMS patients were stimulated.
- Flow cytometry and Multiplex assays were used to quantify TLR-2/TLR-4 expression and cytokine profiles (IL-17, Th17/Tc-17 related cytokines).
- Hydrocortisone treatment, LPS-binding protein (LBP) levels, and clinical/radiological disease activity were evaluated.
Main Results:
- High expression of TLR-2 and TLR-4 on T cells, and increased IL-17-secreting T cells, predicted future RRMS relapses and higher brain lesion counts, even with DMT.
- DMT-treated patients showed heightened T cell responses to TLR agonists, with elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-17, IFN-γ, GM-CSF) correlating with plasma LBP levels.
- Corticosteroids were less effective in reducing Th17/Tc-17 cytokine production in DMT-treated patients who experienced relapses.
Conclusions:
- Persistent circulating Th17 and Tc17 cells with high functional TLR-2 and TLR-4 levels suggest high disease activity in RRMS.
- These findings indicate lower therapeutic efficacy of DMT in RRMS patients with elevated TLR-expressing T cells.
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