Novel costimulatory pathways required for T cell regulation

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The control of T cell tolerance versus immunity in part relies on signals from co-sfimulatory and co-inhibitory receptors that control various activifies ofT cells and modulate the suppressive capacity of regulatory T cells (Treg) and regulatory dendrific cells. 4-1 BB (CDI 37, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, has been characterized as an inducible co-sfimulatory molecule on activated T cells. It's recognized ligand, termed 4-1 BBL (TNFSF9), is a member ofthe TNF super-family. Opposed to the posifive role that 4-1 BB plays in immunity, we have found a novel inhibitoryrole that does not rely on interaction with 4-1 BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness ofT cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammafion at the mucosal interfaces, a phenotype not seen in 4-1 BBL-deficient mice. We have found a deficit of FoxpS+ Treg at the mucosal surfaces in mice lacking 4- 1BB, and an inability of mucosal dendritic cells to display normal regulatory activity and induce the development of FoxpS+ Treg. We will test the hypothesis that 4-1 BB modulafion ofthe acfivity of Treg and regulatory dendrific cells accounts for its role in promofing immune tolerance, and pursue the idea that 4-1 BB partnering with new, previously unrecognized, ligands results in regulation of convenfional T cell immunity. We have found that 4-1 BB can bind to galecfin-3 and galecfin-9, two reported suppressive molecules, and we will determine whether 4-1BB/galecfin interacfions account for 4-1 BB negatively regulafing T cell responsiveness.