Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation
Taylor H. Schreiber, … , Robert B. Levy, Eckhard R. Podack
Taylor H. Schreiber, … , Robert B. Levy, Eckhard R. Podack
Published September 20, 2010
Citation Information: J Clin Invest. 2010;120(10):3629-3640. https://doi.org/10.1172/JCI42933.
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Research Article

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

Abstract

TNF receptor superfamily member 25 (TNFRSF25; also known as DR3, and referred to herein as TNFR25) is constitutively and highly expressed by CD4+FoxP3+ Tregs. However, its function on these cells has not been determined. Here we used a TNFR25-specific agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Tregs in vivo in mice. Signaling through TNFR25 induced rapid and selective expansion of preexisting Tregs in vivo such that they became 30%–35% of all CD4+ T cells in the peripheral blood within 4 days. TNFR25-induced Treg proliferation was dependent upon TCR engagement with MHC class II, IL-2 receptor, and Akt signaling, but not upon costimulation by CD80 or CD86; it was unaffected by rapamycin. TNFR25-expanded Tregs remained highly suppressive ex vivo, and Tregs expanded by TNFR25 in vivo were protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of effector T cells to Tregs in the lung, suppressing IL-13 and Th2 cytokine production, and blocking eosinophil exudation into bronchoalveolar fluid. Our studies define what we believe to be a novel mechanism for Treg control and important functions for TNFR25 in regulating autoaggression that balance its known role in enhancing autoimmunity.

Authors

Taylor H. Schreiber, Dietlinde Wolf, Matthew S. Tsai, Jackie Chirinos, Vadim V. Deyev, Louis Gonzalez, Thomas R. Malek, Robert B. Levy, Eckhard R. Podack

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Figure 4

In vivo Treg expansion by TNFR25 inhibits inflammation in allergic asthma.

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In vivo Treg expansion by TNFR25 inhibits inflammation in allergic asthm...
Allergic asthma was induced by immunization with OVA/alum followed by aerosol challenge with OVA/PBS, as described in Methods. (A) Peripheral blood was collected and analyzed for the fraction of CD4+FoxP3+ cells relative to total CD4+ T cells from OVA/alum-immunized mice compared with nonimmunized mice following treatment with either 4C12 or isotype control antibody. (B) Total lung cells were harvested and analyzed by flow cytometry. The total number of each indicated cell population are shown. (C) The percentage of Tregs out of total CD4+ T cells. (D) BALF was collected 3 days after aerosolization with OVA/PBS. The total number of eosinophils is shown. (E) Total RNA was extracted from total lung cells and used for real-time RT-PCR. Expression of IL-4, IL-5, IL-13, and FoxP3 in 4C12- or isotype control–treated mice is shown relative to saline-aerosolized control lung cells. (F) Lungs were harvested and sectioned for histological sections. H&E and PAS images were obtained for each treatment group; representative images are shown. Data were repeated in 4 independent experiments with at least 3 mice per group per experiment. (G) PAS-stained sections were quantitated using Image J software as described in Methods; 2 representative images were quantitated from each of 5 or more mice from 2 separate experiments. All data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 versus respective control, 1-way ANOVA with Tukey post-test.