The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells and modulate the suppressive capacity of regulatory T cells (Treg) and regulatory dendritic 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-stimulatory molecule on activated T cells. It's recognized ligand, termed 4-1 BBL (TNFSF9), is a member ofthe TNF super-family. Opposed to the positive 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 of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1 BBL-deficient mice. We have found a deficit of Foxp3+ 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 Foxp3+ Treg. We will test the hypothesis that 4-1 BB modulation ofthe activity of Treg and regulatory dendritic cells accounts for its role in promoting immune tolerance, and pursue the idea that 4-1 BB partnering with new, previously unrecognized, ligands results in regulation of conventional 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/galectin interactions account for 4-1 BB negatively regulating T cell responsiveness.

Public Health Relevance

4-1 BB and its ligand(s) are expressed on the surface of many immune cells and are thought to regulate the ability to mount an immune response. By understanding where and when 4-1 BB and its ligand(s) are expressed, and the functional importance of these putative interactions, we will gain knowledge that might lead to ways to either enhance or suppress T cell responses, and so might be therapeutically relevant in a number of disease settings such as in limiting auto immunity.

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