OX40L/OX40 axis impairs follicular and natural Treg function in human SLE
Clément Jacquemin, … , Cécile Contin-Bordes, Patrick Blanco
Clément Jacquemin, … , Cécile Contin-Bordes, Patrick Blanco
Published December 20, 2018
Citation Information: JCI Insight. 2018;3(24):e122167. https://doi.org/10.1172/jci.insight.122167.
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Research Article Immunology

OX40L/OX40 axis impairs follicular and natural Treg function in human SLE

Abstract

Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell–dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.

Authors

Clément Jacquemin, Jean-François Augusto, Marc Scherlinger, Noémie Gensous, Edouard Forcade, Isabelle Douchet, Emeline Levionnois, Christophe Richez, Estibaliz Lazaro, Pierre Duffau, Marie-Elise Truchetet, Julien Seneschal, Lionel Couzi, Jean-Luc Pellegrin, Jean-François Viallard, Thierry Schaeverbeke, Virginia Pascual, Cécile Contin-Bordes, Patrick Blanco

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Figure 4

OX40L-dependent downregulation of Foxp3 expression in Tregs.

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OX40L-dependent downregulation of Foxp3 expression in Tregs. (A and B) T...
(A and B) Tregs (104 cells) were cocultured in the presence or absence of anti-OX40L mAb (10 μg/ml) for 3 days with Eff.T4 cells (104 cells) and either GM-CSF+IL-4 DCs or SLE DCs. (A) Representative histogram showing surface expression of CTLA-4, GITR, and CD25 on Foxp3+ Tregs. (B) Expression of Foxp3 in CD4+CD25hiCD127– Tregs from cocultures with Eff.T4 cells and GM-CSF+IL-4 DCs or SLE DCs with or without anti-OX40L mAb. Representative histogram showing Foxp3 expression in Tregs cultured with GM-CSF+IL-4 DCs (black line), SLE DCs (gray line), and SLE DCs + anti-OX40L mAb (red line) (top). Cumulative data obtained with 4 different GM-CSF+IL-4 DCs and 13 different SLE DCs (bottom). Four independent experiments were undertaken and compared using nonparametric 2-tailed paired Wilcoxon test. *P < 0.05; ***P < 0.001. (C) Expression of Foxp3 in Tregs cultured with or without sOX40L (100 ng/ml). Representative histogram showing Foxp3 expression in Tregs cultured with (gray line) or without (black line) sOX40L (left). Dotted line represents Foxp3 isotype. Cumulative data from 5 independent experiments are shown and compared using nonparametric 2-tailed Mann-Whitney test (right). *P < 0.05. Results are expressed as Foxp3 MFI in Tregs. (D) Expression of Foxp3 in Eff.T4 cells and Tregs cultured for 3 days with OX40L or CD32-transfected L cells. Representative histogram showing Foxp3 expression in Eff.T4 cells (dashed line) and Tregs cultured with OX40L-transfected L cells (gray line) or CD32-tranfected L cells (black line) (left). Cumulative data from 3 independent experiments, compared using nonparametric 2-tailed paired Wilcoxon test (right). *P < 0.05. Results are expressed as Foxp3 MFI in Tregs. (E) Foxp3 expression in CD3+CD4+CD25hi blood cells of HDs and SLE patients. Representative dot plots showing blood CD3+CD4+CD25hiFoxp3+ cells (top). Cumulative data analysis from 9 HDs and 25 SLE patients (bottom). Results are expressed as mean Foxp3 MFI in CD3+CD4+CD25hi cells. Error bars indicate the mean ± SEM. (F) Correlation between proportion of blood OX40L-expressing CD11c+DR+ cells and Foxp3 MFI expression in CD3+CD4+CD25hi blood cells of SLE patients (n = 26). Statistical analysis was performed using Spearman’s rank correlation test.