Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation.
We identify the tumor necrosis factor receptor superfamily 25 (TNFRSF25)/TNFSF15 pair as critical trigger for allergic lung inflammation, which is a cardinal feature of asthma. TNFRSF25 (TNFR25) signals are required to exert T helper cell 2 (Th2) effector function in Th2-polarized CD4 cells and co-stimulate interleukin (IL)-13 production by glycosphingolipid-activated NKT cells. In vivo, antibody blockade of TNFSF15 (TL1A), which is the ligand for TNFR25, inhibits lung inflammation and production of Th2 cytokines such as IL-13, even when administered days after airway antigen exposure. Similarly, blockade of TNFR25 by a dominant-negative (DN) transgene, DN TNFR25, confers resistance to lung inflammation in mice. Allergic lung inflammation-resistant, NKT-deficient mice become susceptible upon adoptive transfer of wild-type NKT cells, but not after transfer of DN TNFR25 transgenic NKT cells. The TNFR25/TL1A pair appears to provide an early signal for Th2 cytokine production in the lung, and therefore may be a drug target in attempts to attenuate lung inflammation in asthmatics.
Fang
Lei
L
Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Adkins
Becky
B
Deyev
Vadim
V
Podack
Eckhard R
ER
D000818:Animals; D000911:Antibodies, Monoclonal; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006224:Cricetinae / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology*; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000503:physiopathology*; D008168:Lung / Q000276:immunology / Q000503:physiopathology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; C506034:Tnfrsf25 protein, mouse; D007073:Immunoglobulin E; D010047:Ovalbumin