Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple Sclerosis Patients at Higher Risk of Therapy Failure

Joana Hygino; Marisa C Sales; Priscila M Sacramento; Taissa M Kasahara; Júlio César Costa da Silva; Rafaela Bilhão; Regis M Andrade; Cláudia Cristina Ferreira Vasconcelos; Cleonice A M Bento

doi:10.2147/JIR.S476110

Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple Sclerosis Patients at Higher Risk of Therapy Failure

J Inflamm Res. 2024 Nov 14:17:8775-8797. doi: 10.2147/JIR.S476110. eCollection 2024.

Affiliations

¹ Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.
² Post-Graduate Program in Microbiology, University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.
³ Post-graduate Program in Molecular and Cellular Biology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.
⁴ Department of General Medicine, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.
⁵ Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.

^# Contributed equally.

Abstract

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.

Keywords: LPS-binding protein; T cells; Th17; multiple sclerosis; toll-like receptors.

Grants and funding

This study was supported by the Fundação de Amparo à Pesquisa Carlos Chagas Filho (FAPERJ, grant number: E-26/203.909/2021) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant number: 301.780/2017-0).