Targeting the TNFRSF25 Pathway to Shift the Balance Between Inflammation and Immunosuppression

The dynamic immunomodulatory properties of the co-stimulator TNF receptor superfamily member 25 (TNFRSF25) make it a compelling therapeutic target for context-dependent regulation of T cell responses and immune stability

How it works

  • TNFRSF25 is highly and constitutively expressed on resting FoxP3+ T regulatory (Treg) cells.
  • TNFRSF25 recognizes the cytokine TNF-like ligand 1A (TL1A) secreted by several cell types including dendritic cells, monocytes, macrophages, and plasma cells.
  • In the absence of a danger or activating signal, co-stimulation of TNFRSF25 results in the selective expansion of immunosuppressive FoxP3+ CD4+ Treg cells that can reduce inflammation.
  • Conversely, co-stimulation of TNFRSF25 in the presence of a danger or activating signal (arising from infection or cancer) promotes the expansion of inflammatory effector T cells that play a critical role in mediating anti-tumor and anti-pathogen responses.

TNFRSF25 by the numbers


Grants Awarded


Clinical Targets



Advantages of Targeting TNFRSF25

  • TNFRSF25-mediated expansion of Treg cells in the absence of a danger signal is accompanied by increased expression of immunosuppressive markers and activity.
  • TNFRSF25 agonists have shown benefit in several preclinical models including rheumatoid arthritis1, diabetic retinopathy2, allergic lung inflammation3, inflammatory bowel disease4, infectious disease5, and hematopoietic stem cell transplant6-7.
  • Preclinical studies demonstrate a low toxicity profile associated with TNFRSF25 targeting.
  • Single agent with unique context dependent capability to enhance or suppress inflammatory immune responses.

TNFRSF25-Targeting Development Programs

  • Oncology: PTX-35 is a humanized monoclonal antibody agonist of TNFRSF25 currently being evaluated in a Phase I clinical trial as an immunotherapy for the treatment of solid tumors.
  • Inflammation: Preclinical studies investigating the potential of PTX-35 for restoring or protecting the immunological balance in multiple inflammatory disorders are underway.


1 Croft et al. Beyond TNF: TND superfamily cytokines as targets for the treatment of rheumatic disease. 2017

2Zhang et al. Changes in TL1A levels and Associated Cytokines During Pathogenesis of Diabetic Retinopathy. 2017

3Schreiber et al. Therapeutic Treg Expansion in Mice by TNFRSF25 Prevents Allergic Lung Inflammation. 2010

4Li et al. Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn’s Disease-like Ileitis. 2018

5Twohig et al. The Death Receptor 3/TL1A Pathway is Essential for Efficient Development of Antiviral CD4+ and CD8+ T-cell Immunity. 2012

6Wolf et al. Marked in vivo Donor Treg Expansion via IL-2 and TL1A-Ig stimulation ameliorates GVHD but preserves GVL in recipients post-HSCT. 2017

7Mavers et al. Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T cell Expansion and Activation With Reduction in Graft-Versus-Host Disease. 2019