Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

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

Research output: Contribution to journalArticle

92 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3629-3640
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number10
DOIs
StatePublished - Oct 1 2010

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Pneumonia
T-Lymphocytes
Interleukin-13
Tumor Necrosis Factor Receptors
Interleukin-2 Receptors
Sirolimus
Autoimmunity
Eosinophils
Asthma
Monoclonal Antibodies
Cytokines
Lung
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schreiber, T. H., Wolf, D., Tsai, M. S., Chirinos, J., Deyev, V. V., Gonzalez, L., ... Podack, E. R. (2010). Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. Journal of Clinical Investigation, 120(10), 3629-3640. https://doi.org/10.1172/JCI42933

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. / Schreiber, Taylor H.; Wolf, Dietlinde; Tsai, Matthew S.; Chirinos, Jackie; Deyev, Vadim V.; Gonzalez, Louis; Malek, Thomas; Levy, Robert B; Podack, Eckhard R.

In: Journal of Clinical Investigation, Vol. 120, No. 10, 01.10.2010, p. 3629-3640.

Research output: Contribution to journalArticle

Schreiber, TH, Wolf, D, Tsai, MS, Chirinos, J, Deyev, VV, Gonzalez, L, Malek, T, Levy, RB & Podack, ER 2010, 'Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation', Journal of Clinical Investigation, vol. 120, no. 10, pp. 3629-3640. https://doi.org/10.1172/JCI42933
Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L et al. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. Journal of Clinical Investigation. 2010 Oct 1;120(10):3629-3640. https://doi.org/10.1172/JCI42933
Schreiber, Taylor H. ; Wolf, Dietlinde ; Tsai, Matthew S. ; Chirinos, Jackie ; Deyev, Vadim V. ; Gonzalez, Louis ; Malek, Thomas ; Levy, Robert B ; Podack, Eckhard R. / Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 10. pp. 3629-3640.
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