Abstract
Abstract Tumor necrosis factor (TNF) superfamily member 15 (TL1A) is the natural ligand for TNFRSF25. We previously reported that TNFRSF25 stimulation with an agonist antibody 4C12 selectively expands pre-existing Tregs in vivo. To compare TL1A to 4C12, we generated a soluble mouse hexameric TL1A-Ig fusion protein. TL1A-Ig mediates proliferation of Foxp3+ Treg in vitro. TNFRSF25 stimulation by TL1A-Ig in vivo induces expansion of Tregs to 30-35% of all CD4+ T cells in the peripheral blood within 5 days of treatment. With daily injections of TL1A-Ig elevated levels of Tregs can be maintained for at least 20 days. TL1A-Ig expanded Tregs express high levels of the activation/memory markers KLRG1 and CD103 and are highly suppressive ex vivo. TL1A-Ig mediated Treg expansion in vivo is protective against allergic lung inflammation by reversing the ratio of Tconvs:Tregs in the lung and blocking eosinophil exudation into the bronchoaveolar fluid. We tested the potential of TNFRSF25 agonists in transplant tolerance in several models. (1) TL1A-Ig injections 12 days after injection of allogeneic splenocytes caused diminished alloantigen-specific T cell responses in mixed lymphocyte reactions as compared to mice treated with allogeneic splenocytes only. (2) TNFRSF25 mediated Treg expansion in vivo significantly prolonged allogeneic skin graft survival. Thus, TL1A-Ig fusion proteins are potent and tightly controllable agents that may provide therapeutic benefit in asthma and transplant tolerance.
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