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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI089624-04
Application #
8495230
Study Section
Special Emphasis Panel (ZAI1-SV-I)
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$438,137
Indirect Cost
$206,196
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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