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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

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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 3

SLE DCs do not confer Tregs resistance to effector T4 cells.

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SLE DCs do not confer Tregs resistance to effector T4 cells.
(A–C) Allog...
(A–C) Allogenic HD Eff.T4 cells (5 × 104) were cocultured either with GM-CSF+IL-4 DCs or SLE DCs (5 × 103) for 3 days. At 3 days, Eff.T4 cells were purified from culture and were further cocultured with GM-CSF+IL-4 DCs in the presence or absence of Tregs at a Eff.T4/Tregs/DC ratio of 1:1:0.1 respectively. (A) Analysis of Eff.T4 cell proliferation, performed by (3H) thymidine incorporation measurement. (B) Analysis of TNFR2 surface expression on CD25– Eff.T4 cells, CD25+ active Eff.T4 cells, and CD25hi Tregs from GM-CSF+IL-4 DC or SLE DC cocultures. Representative dot plot (top) and histogram (bottom) showing TNFR2 expression on CD25– Eff.T4 cells, CD25+ active Eff.T4 cells, and CD25hi Tregs. (C) Cumulative data obtained from 3 cultures with purified T cells from GM-CSF+IL-4 or SLE DC cocultures represent the percentage of cells expressing surface TNFR2. Error bars indicate the mean ± SEM, n = 3.

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