Cloning, expression, and functional characterization of TL1A-Ig
| Autor: | Matthew S. Tsai, Vadim Deyev, Eckhard R. Podack, Dietlinde Wolf, Samia Q. Khan, Taylor H. Schreiber |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Tumor Necrosis Factor Ligand Superfamily Member 15
Recombinant Fusion Proteins Immunology Population chemical and pharmacologic phenomena CHO Cells Transfection Mice In vivo Genes Reporter Cell Line Tumor Cricetinae medicine Respiratory Hypersensitivity Immunology and Allergy Animals Cloning Molecular education education.field_of_study MHC class II biology T-cell receptor FOXP3 hemic and immune systems Eosinophil Flow Cytometry Fusion protein Cell biology Mice Inbred C57BL Mutagenesis Insertional medicine.anatomical_structure biology.protein NIH 3T3 Cells Immunoglobulin Heavy Chains Ex vivo Plasmids |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 190(4) |
| ISSN: | 1550-6606 |
| Popis: | TNF superfamily member 15 (TL1A) is the ligand for TNFR superfamily (TNFRSF)25. We previously reported that TNFRSF25 stimulation with an agonist Ab, 4C12, expands pre-existing CD4+Foxp3+ regulatory T cells (Tregs) in vivo. To determine how the physiological ligand differs from the Ab, we generated a soluble mouse TL1A-Ig fusion protein that forms a dimer of TL1A trimers in solution with an apparent molecular mass of 516 kDa. In vitro, TL1A-Ig mediated rapid proliferation of Foxp3+ Tregs and a population of CD4+Foxp3− conventional T cells. TL1A-Ig also blocked de novo biogenesis of inducible Tregs and it attenuated the suppressive function of Tregs. TNFRSF25 stimulation by TL1A-Ig in vivo induced expansion of Tregs such that they increased to 30–35% of all CD4+ T cells in the peripheral blood within 5 d of treatment. Treg proliferation in vivo was dependent on TCR engagement with MHC class II. Elevated Treg levels can be maintained for at least 20 d with daily injections of TL1A-Ig. TL1A-Ig–expanded Tregs expressed high levels of activation/memory markers KLRG1 and CD103 and were highly suppressive ex vivo. TL1A-Ig–mediated Treg expansion in vivo was protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of conventional T cells to Tregs in the lung and blocking eosinophil exudation into the bronchoalveolar fluid. Thus, TL1A-Ig fusion proteins are highly active and tightly controllable agents to stimulate Treg proliferation in vivo, and they are uniquely able to maintain high levels of expanded Tregs by repeated administration. |
| Databáze: | OpenAIRE |
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