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Human TNFR2 Exhibits Bi-Directional Control over Regulatory T Cells
Monday, March 3, 2014: 2:00 PM
Room 15AB (Convention Center)
Denise L. Faustman, MD, PhD, ,
Background: The homeostatic functions of CD4+ regulatory T-cells (Treg) protect against autoimmunity, cancer and infections, but mechanisms governing Treg activity are ill-defined.  We hypothesized that tumor necrosis factor receptor 2 (TNFR2) may control Treg functions, considering that TNFR2 is highly expressed on human Tregs.  Methods: Effects of TNFR2 monoclonal antibodies (moAbs) on Treg proliferation, signaling, phenotype, and function were studied by multiple in vitro assays using isolated fresh human CD4+ and CD25hi coexpressing T cells from >100 donors. Antibody performance was compared to standard Treg expansion methods and categorized as agonist, antagonist or neutral in activity. Results: Two antibodies exclusively acted as either a TNFR2 agonist or antagonist.  In vitro the newly identified TNFR2 agonist induced proliferation of enriched human Tregs into phenotypically homogeneous populations of effector Tregs (FOXP3hiCD45RO+CD25hiHLA-DR+CTLA4+,CD127-CXCR3-).  Conversely, the TNFR2 antagonist suppressed human Treg proliferation.  When Tregs were co-incubated with their target CD8+ T-cells, the agonist-treated Tregs suppressed CD8+ proliferation, whereas the antagonist had negligible effects.  The two ligands also triggered different downstream intracellular Treg signaling, with the agonist upregulating TRAF2, FOXP3 and cIAP2.  Conclusions: The findings show that certain TNFR2 ligands can act as antagonists or agonists by exerting opposing actions in human cells regarding Treg proliferation, signaling, and target cell activity.  TNFR2 has the potential for bidirectional control over Treg homeostatic functions in humans, opening new clinical opportunities for Treg expansion or suppression.