IL-23 and monocyte interactions redirect human Th17.1 cells to an IL-17AhighIFN-γhigh potentially pathogenic profile
- 1Department of Rheumatology, Erasmus MC, University Medical Center , ,
- 2Department of Immunology, Erasmus MC, University Medical Center , ,
Abstract
Introduction: IL-23–targeted therapies have demonstrated clinical efficacy in psoriatic arthritis (PsA), primarily through the reduction of IL-17A–driven inflammation. Consequently, most studies have focused on classical, high IL-17A-producing, CCR6 ⁺ CXCR3 ⁻ CCR4 ⁺ Th17 cells. In contrast, the impact of IL‑23 signaling on CCR6 ⁺ CXCR3 ⁺ CCR4 ⁻ Th17.1 cells —traditionally characterized by high IFN-γ and low IL-17A production—remains largely unexplored, despite their recognized pathogenicity in autoimmune disease. The aim of this study was to characterize the effects of IL-23 on human memory Th17.1 cells.
Methods: Peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early PsA were stimulated in the presence of IL-23 or anti-IL-23 antibody before quantifying IL-17A and IFN-γ secretion. Additionally, human memory CCR6 ⁻ Th1, CCR6 ⁺ Th17.1 and CCR6+ Th17 cells from healthy donors were sorted and analyzed ex vivo for IL23R , TBX21 and RORC expression using RT-qPCR. Sorted Th17.1, Th17 and Th1 cells were subsequently cultured alone or cocultured with IL-23-producing monocytes. Cultures received either exogenous IL-23 or IL-23 inhibition before analyzing IL-17A and IFN-γ secretion.
Results: As expected, IL-23 stimulation induced IL-17A in PsA PBMCs, whereas IL-23 inhibition reduced IL-17A secretion but did not affect IFN-γ. In healthy donor PBMCs, ex vivo IL-23R expression was restricted to memory CCR6 ⁺ Th17 and Th17.1 cells. Remarkably, IL-23 stimulation of Th17.1 cells significantly increased IFN-γ without affecting IL-17A secretion. Compared to monoculture, cocultures with monocytes increased IFN-γ secretion in Th17.1 and classical Th1 cells, and IL-17A secretion in Th17 and Th17.1 cells. Additional IL-23 stimulated IL-17A in both Th17 and Th17.1 cocultures, while unexpectedly reducing IFN-γ in Th17.1 cells. In contrast, IL-23 inhibition reduced IL-17A secretion in Th17 and Th17.1 cells without affecting IFN-γ production.
Conclusion: IL-23 exerts distinct effects on Th17.1 compared to Th17 cells. We show a role for IL-23 in IFN-γ upregulation in Th17.1 cells, which is reversed in the presence of monocytes. In co-culture with monocytes, Th17.1 cells progress to a pathogenic IL-17A high IFN-γ high profile, which is further elevated by IL-23 stimulation and reduced upon IL-23 neutralization. We show that IL-23 drives Th17.1 plasticity and underscore the therapeutic relevance of neutralizing IL-23 in the suppression of these pathogenic IL-17A high IFN-γ high Th17.1 cells.
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BibTeX
@article{heeswijk2026il23,
title = {{IL-23 and monocyte interactions redirect human Th17.1 cells to an IL-17AhighIFN-γhigh potentially pathogenic profile}},
author = {Bennie van Heeswijk and Wida Razawy and Nadine Davelaar and Anne-Marie M.C. Mus and Patrick S. Asmawidjaja and Pieter J.M. Leenen and Erik Lubberts},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1793184},
url = {https://europepmc.org/article/PMC/PMC13661559},
note = {CC BY},
}
RIS
TY - JOUR
TI - IL-23 and monocyte interactions redirect human Th17.1 cells to an IL-17AhighIFN-γhigh potentially pathogenic profile
AU - Bennie van Heeswijk
AU - Wida Razawy
AU - Nadine Davelaar
AU - Anne-Marie M.C. Mus
AU - Patrick S. Asmawidjaja
AU - Pieter J.M. Leenen
AU - Erik Lubberts
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1793184
UR - https://europepmc.org/article/PMC/PMC13661559
AB - Introduction: IL-23–targeted therapies have demonstrated clinical efficacy in psoriatic arthritis (PsA), primarily through the reduction of IL-17A–driven inflammation. Consequently, most studies have focused on classical, high IL-17A-producing, CCR6 ⁺ CXCR3 ⁻ CCR4 ⁺ Th17 cells. In contrast, the impact of IL‑23 signaling on CCR6 ⁺ CXCR3 ⁺ CCR4 ⁻ Th17.1 cells —traditionally characterized by high IFN-γ and low IL-17A production—remains largely unexplored, despite their recognized pathogenicity in autoimmune disease. The aim of this study was to characterize the effects of IL-23 on human memory Th17.1 cells. Methods: Peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early PsA were stimulated in the presence of IL-23 or anti-IL-23 antibody before quantifying IL-17A and IFN-γ secretion. Additionally, human memory CCR6 ⁻ Th1, CCR6 ⁺ Th17.1 and CCR6+ Th17 cells from healthy donors were sorted and analyzed ex vivo for IL23R , TBX21 and RORC expression using RT-qPCR. Sorted Th17.1, Th17 and Th1 cells were subsequently cultured alone or cocultured with IL-23-producing monocytes. Cultures received either exogenous IL-23 or IL-23 inhibition before analyzing IL-17A and IFN-γ secretion. Results: As expected, IL-23 stimulation induced IL-17A in PsA PBMCs, whereas IL-23 inhibition reduced IL-17A secretion but did not affect IFN-γ. In healthy donor PBMCs, ex vivo IL-23R expression was restricted to memory CCR6 ⁺ Th17 and Th17.1 cells. Remarkably, IL-23 stimulation of Th17.1 cells significantly increased IFN-γ without affecting IL-17A secretion. Compared to monoculture, cocultures with monocytes increased IFN-γ secretion in Th17.1 and classical Th1 cells, and IL-17A secretion in Th17 and Th17.1 cells. Additional IL-23 stimulated IL-17A in both Th17 and Th17.1 cocultures, while unexpectedly reducing IFN-γ in Th17.1 cells. In contrast, IL-23 inhibition reduced IL-17A secretion in Th17 and Th17.1 cells without affecting IFN-γ production. Conclusion: IL-23 exerts distinct effects on Th17.1 compared to Th17 cells. We show a role for IL-23 in IFN-γ upregulation in Th17.1 cells, which is reversed in the presence of monocytes. In co-culture with monocytes, Th17.1 cells progress to a pathogenic IL-17A high IFN-γ high profile, which is further elevated by IL-23 stimulation and reduced upon IL-23 neutralization. We show that IL-23 drives Th17.1 plasticity and underscore the therapeutic relevance of neutralizing IL-23 in the suppression of these pathogenic IL-17A high IFN-γ high Th17.1 cells.
SN - 1664-3224
ER -