Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation.
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.
Schreiber
Taylor H
TH
Sheila and David Fuente Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Wolf
Dietlinde
D
Tsai
Matthew S
MS
Chirinos
Jackie
J
Deyev
Vadim V
VV
Gonzalez
Louis
L
Malek
Thomas R
TR
Levy
Robert B
RB
Podack
Eckhard R
ER
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000819:agonists / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt