cell activation is dependent on TCR recognition and cooperating signaling systems that provide positive or negative responses governing the quality of a T cell response. Cosignaling systems are emerging as important targets to enhance the immune response to tumor or pathogens and attenuate autoimmune diseases, yet these systems remain inadequately defined. Two major functional groups of cosignaling regulators are recognized: receptors with an Ig-like fold and members of the TNF receptor superfamily. We identified a novel inhibitory cosignaling pathway between HVEM (herpesvirus entry mediator;TNFRSF14) and BTLA (B-T lymphocyte attenuator), connecting the TNFR and Ig cosignaling families. The HVEM-BTLA interaction functions as an inhibitory pathway for T cell activation through an ITIM motif of BTLA. By contrast, the LIGHT-HVEM pathway provides positive cosignaling system in T cell activation particularly in mucosal inflammation, but the functional consequences of LIGHT-HVEM-BTLA signaling are unknown. We propose the LIGHT-HVEM-BTLA interaction provides a critical control mechanism for the regulation T cell activation, which is the overall focus of this application. A variety of reagents have been developed for this project including specific agonists and antagonists, e.g., decoy receptors, specific agonist antibodies and ligands for use with human systems, and mice genetically deficient in HVEM, LIGHT, and BTLA.
Two aims are proposed to address the role of LIGHT-HVEM-BTLA system in T cell activation.
The first aim addresses the structural features that allow HVEM to serve as a molecular switch between positive and inhibitory cosignaling. Structural and cell-cell interaction models utilizing a human culture system will be used to define the directionality of HVEM-BTLA interaction and how LIGHT controls the activation of BTLA and HVEM.
Aim 2 is directed at defining LIGHT-HVEM-BTLA system using in vivo models of lung inflammation that are controlled by both CD4 and CDS T cells, involving Type 1 or Type 2 cytokines by assessing responses in HVEM-, BTLA-, or LIGHT-deficient mice and OT-II and OT-I TCR transgenic HVEM-deficient mice. Collectively, this project will provide a comprehensive perspective on the role of LIGHT-HVEM-BTLA cosignaling system in a lung inflammation model providing the foundation for exploiting this system as a therapeutic intervention. Lay audience: We discovered several proteins that form a communication network between white bloods cells, which control inflammation. Altering this communication system may help stop unwanted inflammation that occurs in autoimmune diseases, or to enhance immunity to viruses or cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067890-04
Application #
7848859
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Dong, Gang
Project Start
2007-05-01
Project End
2010-07-31
Budget Start
2010-05-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$106,274
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19
Correa, Ricardo G; Krajewska, Maryla; Ware, Carl F et al. (2014) The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling. Oncotarget 5:1666-82
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Ware, Carl F (2013) Protein therapeutics targeted at the TNF superfamily. Adv Pharmacol 66:51-80
Šedý, John R; Bjordahl, Ryan L; Bekiaris, Vasileios et al. (2013) CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells. J Immunol 191:828-36
Bekiaris, Vasileios; Šedý, John R; Macauley, Matthew G et al. (2013) The inhibitory receptor BTLA controls ?? T cell homeostasis and inflammatory responses. Immunity 39:1082-1094
Flynn, Rachel; Hutchinson, Tarun; Murphy, Kenneth M et al. (2013) CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PLoS One 8:e77991
Bekiaris, Vasileios; Šedy, John R; Rossetti, Maura et al. (2013) Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-?? and are elevated in rheumatoid arthritis. J Immunol 191:4611-8

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