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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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 5

TNFR25 stimulation leads to Treg expansion in vivo by inducing proliferation of existing CD4+FoxP3+CD25int cells.

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TNFR25 stimulation leads to Treg expansion in vivo by inducing prolifera...
(A) FIR mice were treated with IgG or 4C12 on day 0, and splenocytes were harvested 4 days later and analyzed by flow cytometry. Representative plots are shown. (B) Mean CD25hi and CD25int Treg numbers in splenocytes 4 days after the indicated treatments. (C) Representative dot plots were pregated on CD4+FoxP3+ cells. Percentages indicate the contribution of each phenotype toward the total fraction of CD4+FoxP3+ cells. (D) Mean proportion of Ki67+ and Ki67– cells among CD25hi and CD25int Tregs as in A. Data are mean ± SEM. (E–H) CD4+FoxP3– and CD4+FoxP3+ cells were sorted from CD45.2+ FIR mice to greater than 99% purity, and 2 × 106 cells from each subset were adoptively transferred into CD45.1 congenic B6-SJL mice. Mice were injected i.p. 24 hours later with 20 μg 4C12 or IgG. (E and F) Histograms showing percentage of transferred CD45.2+FoxP3+ and CD45.2+FoxP3– cells out of total CD4+ cells on day 5 after adoptive transfer. (G and H) Kinetics of transferred cell contraction following 4C12 or hamster IgG treatment. Data are mean ± SEM for 3 mice per group for each of 2 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.