An agonist TIGIT mab suppresses regulatory T cell activity via an IL-2-mediated mechanism

Abstract The co-inhibitory receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a 26 kDa immunoglobulin domain-containing transmembrane protein that contains both intracellular ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif) and ITT (Immunoreceptor Tail Tyrosine) like domains and is found on the surface of Natural Killer and T cells. CD155 (or the poliovirus receptor) and CD112 (or Nectin-2) are natural ligands for both TIGIT and the activating receptor CD226 (or DNAM-1). In addition to the complexity of the TIGIT/DNAM-1 interplay, TIGIT has been demonstrated to drive both cell intrinsic and extrinsic functions. TIGIT binding to CD155 on Dendritic cells can drive reduction of pro-inflammatory cytokines while inducing tolerogenic cytokine secretion (Yu, 2009). More recently regulatory T cells have been demonstrated to express high levels of TIGIT and upon ligation have been demonstrated to induce effector molecules like FGL2 and reported to promote suppressive function (Joller, 2014). We’ve identified an agonist anti-TIGIT monoclonal antibody, TGTB227, that inhibits T cell responses in vitro in both cellular reporter assays and primary memory T cell assays. TGTB227 is a human IgG1k mab that reduced the expression of the transcription factor, Foxp3, on Tregs. Moreover, TGTB227, but not the related TGTB277, reduced the functional suppressive ability of both natural and induced Tregs. Finally, these data support a TIGIT driven intrinsic CD25/IL-2-dependent mechanism for the modulation of Treg activity.