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 2

Circulating DCs from SLE patients suppress Treg function in an OX40L-dependent manner.

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Circulating DCs from SLE patients suppress Treg function in an OX40L-dep...
(A–C) Blood-purified antigen-presenting cells (APCs) from active SLE (aSLE) patients, inactive SLE (iSLE) patients, or healthy donors (HD) were cultured in the presence of allogeneic Eff.T4 cells and Tregs at a 5:1:1 ratio, respectively, with or without blocking anti-OX40L mAb. An isotype control mouse IgG1 was used when indicated. Treg-suppressive function was calculated as described above. (A) This SLE patients’ cells, used in this representative experiment, were clinically active, and his disease activity score (SLEDAI) was 16. (B) Cumulative data obtained from 5 aSLE (SLEDAI: 29, 4, 4 (clinical activity), 16, and 7, respectively) and 5 iSLE patients (SLEDAI: 0, 0, 0, 4 (biological activity only), 1, respectively) and 7 HD APCs. Statistical analyses were undertaken using the Kruskal-Wallis test followed by Dunn’s multiple comparison correction. Error bars indicate the mean ± SEM. (C) Correlation between Treg-suppressive function and circulating OX40L-expressing DCs. Statistical analysis was performed using Spearman’s rank correlation test. (D) Skin biopsies from SLE patients were analyzed for OX40L (in red) and Foxp3 (in green) expression by immunofluorescence. In a cell infiltrate, yellow arrowheads show Foxp3-expressing Tregs in close contact with OX40L-expressing cells denoted by white arrowheads. Scale bar: 10 μm. Data are representative of 3 patients and controls. *P < 0.05, ***P < 0.0001.