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 1

TNFR25 stimulates rapid proliferation of CD4+FoxP3+ cells in vivo.

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TNFR25 stimulates rapid proliferation of CD4+FoxP3+ cells in vivo. (...
(A) Differential expression of TNFR25, GITR, OX40, and 4-1BB on CD4+FoxP3– Tconvs and CD4+FoxP3+ Tregs. TNFRSF expression was determined by flow cytometry on highly purified Tconvs and Tregs from splenocytes harvested from untreated FIR mice. (B) Kinetics and dose-dependent expansion of Tregs in peripheral blood after 4C12 injection. FIR mice were injected i.p. with the indicated amounts of purified 4C12. The mice were bled daily, and FoxP3-RFP expression was analyzed in peripheral blood cells by flow cytometry. (C) Treg expansion was compared after treatment with other TNFR-agonistic antibodies. Mice were injected i.p. with the indicated antibodies (100 μg) on day 0. Mice were bled daily as in B for 6 days, and the percentage of peripheral blood Tregs relative to total CD4+ T cells on day 4 was determined. Data were reproduced in more than 8 independent experiments. Error bars indicate mean ± SEM. Significance was determined by Student’s t test (B) or 1-way ANOVA with Tukey post-test (C). *P < 0.05; **P < 0.01; ***P < 0.001.