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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Gaddis, Dalia E; Padgett, Lindsey E; Wu, Runpei et al. (2018) Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis. Nat Commun 9:1095
Madireddi, Shravan; Eun, So-Young; Mehta, Amit K et al. (2017) Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9. J Immunol 199:2721-2728
Park, Yoon; Jin, Hyung-Seung; Lopez, Justine et al. (2016) SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat Immunol 17:286-96
Eun, So-Young; Lee, Seung-Woo; Xu, Yanfei et al. (2015) 4-1BB ligand signaling to T cells limits T cell activation. J Immunol 194:134-41
Aki, Daisuke; Zhang, Wen; Liu, Yun-Cai (2015) The E3 ligase Itch in immune regulation and beyond. Immunol Rev 266:6-26
Lee, Jee H; Elly, Chris; Park, Yoon et al. (2015) E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1? to Maintain Regulatory T Cell Stability and Suppressive Capacity. Immunity 42:1062-74
Krause, Petra; Morris, Venetia; Greenbaum, Jason A et al. (2015) IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis. Nat Commun 6:7055
Park, Yoon; Jin, Hyung-seung; Aki, Daisuke et al. (2014) The ubiquitin system in immune regulation. Adv Immunol 124:17-66
Jones, Carmen Baca; Pagni, Philippe P; Fousteri, Georgia et al. (2014) Regulatory T cells control diabetes without compromising acute anti-viral defense. Clin Immunol 153:298-307
Madireddi, Shravan; Eun, So-Young; Lee, Seung-Woo et al. (2014) Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. J Exp Med 211:1433-48

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