Program Director/Principal Investigator (Last, First, Middle): Croft, Michael 2 R01 AI042944-10A2 PROJECT SUMMARY/ABSTRACT 4-1BB (CD137), a member of the TNFR superfamily, strongly influences immune cell function in many inflammatory situations. 4-1BB was originally described as a costimulatory molecule and binding to its known ligand, 4-1BBL, a member of the TNF family, is thought to enhance immune responses and the cross-talk between T cells and APC. However, recent data have suggested that 4-1BB biology is much more complex, and that 4-1BB can also play a regulatory or negative role during immune responses. With 4-1BB-deficient mice and using T cells that cannot express 4-1BB, we have found that the initial role, and perhaps its primary role, is an inhibitory rather than stimulatory action. The absence of 4-1BB, in gene-deficient animals, leads to deregulated dendritic cell (DC) development;enhanced responsiveness of T cells to specific antigen;and spontaneous inflammation and autoimmune-type symptoms that develop with age. The molecular basis of these inhibitory activities are unknown. We have found that suppression of myelopoiesis and DC differentiation is due to 4-1BBL delivering inhibitory signals to bone marrow progenitor cells. We also hypothesize that 4-1BB signaling to peripheral T cells can generate both effector cells and regulatory T cells depending on the context in which these signals are received. The studies in this grant will investigate how 4-1BB exerts its modulatory actions through bidirectional cross-talk with 4-1BBL that regulate T cell responsiveness to antigen and hematopoiesis. We will determine how 4-1BB interacting with 4-1BBL controls myeloid and monocyte progenitors that lead to dendritic cell development, and how 4-1BB and 4-1BBL interactions modulate the balance between effector and regulatory T cells that may contribute to maintenance of tolerance and prevention of autoimmune disease.

Public Health Relevance

4-1BB 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. 4-1BB provides essential signals to a T cell to allow it to continue dividing late in its response, and to suppress excessive death. However, 4-1BB interactions also act as a rate- limiting step to control initial T cell division and expansion as well as development of dendritic cells. By understanding where and when 4-1BB 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 autoimmunity, or augmenting the ability to respond to cancerous cells or infectious pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042944-11
Application #
7842626
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
1998-04-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
11
Fiscal Year
2010
Total Cost
$377,800
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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
Ma, Jianhui; Bang, Bo-Ram; Lu, Jiawei et al. (2013) The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation. Sci Signal 6:ra87
Bae, Jun-Sang; Choi, Joong-Kook; Moon, Ji-Hoi et al. (2012) Novel transmembrane protein 126A (TMEM126A) couples with CD137L reverse signals in myeloid cells. Cell Signal 24:2227-36
Lee, Seung-Woo; Park, Yunji; Eun, So-Young et al. (2012) Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. J Immunol 189:2697-701
Zhao, Yuan; Croft, Michael (2012) Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells. Immunol Lett 141:220-6
Lee, Seung-Woo; Choi, Heonsik; Eun, So-Young et al. (2011) Nitric oxide modulates TGF-beta-directive signals to suppress Foxp3+ regulatory T cell differentiation and potentiate Th1 development. J Immunol 186:6972-80
Hsieh, En Hui; Fernandez, Xiomara; Wang, Jing et al. (2010) CD137 is required for M cell functional maturation but not lineage commitment. Am J Pathol 177:666-76
Humphreys, Ian R; Lee, Seung-Woo; Jones, Morgan et al. (2010) Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells. Eur J Immunol 40:2762-8
Salek-Ardakani, Shahram; Croft, Michael (2010) Tumor necrosis factor receptor/tumor necrosis factor family members in antiviral CD8 T-cell immunity. J Interferon Cytokine Res 30:205-18

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