LIGHT is a recently discovered TNF super family cytokine expressed by activated T cells, dendritic cells (DC) and monocytes. It binds to two receptors: HVEM and the lymphotoxin (LT) b receptor. LIGHT has been reported to co-stimulate T cells during priming and to promote Th1 cytokine synthesis. Consistent with this, we and other groups have reported that constitutive LIGHT expression by T cells of transgenic mice leads to inflammation of the intestine and other organs. By contrast, using a colitis model that relies upon CD4+ T cell transfer to immune deficient recipients, we have found that the normal expression of LIGHT by APC slows disease progression. We therefore propose that LIGHT can have opposing effects: promoting inflammation when over expressed in T cells and preventing it when expressed normally in APC. The experiments in this proposal will use the T cell transfer model of colitis induction to determine how LIGHT expression by APC modulates colitis pathogenesis, analyzing the cell types affected, the receptor(s) LIGHT interacts with to modulate disease, and the cell types expressing these receptors. In vitro experiments will be carried out to identify possible mechanisms for the in vivo effects. We also will determine how constitutive expression of LIGHT by T cells leads to accelerated disease. The experiments in this proposal will provide a thorough analysis of the contrasting roles of LIGHT expression in colitis pathogenesis in mice, which could provide the basis for understanding its role in other autoimmune conditions. Blockade of LT/LIGHT signals is currently being explored as a treatment for human autoimmune diseases. The experimental results derived from the proposed experiments could provide important insights into the mechanisms for the beneficial and potentially harmful effects of such a blockade.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Immunological Sciences Study Section (IMS)
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Rothermel, Annette L
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La Jolla Institute
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Seo, Goo-Young; Shui, Jr-Wen; Takahashi, Daisuke et al. (2018) LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection. Cell Host Microbe 24:249-260.e4
Herro, Rana; Shui, Jr-Wen; Zahner, Sonja et al. (2018) LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. J Exp Med 215:415-422
Edwards, Rebecca G; Kopp, Sarah J; Ifergan, Igal et al. (2017) Murine Corneal Inflammation and Nerve Damage After Infection With HSV-1 Are Promoted by HVEM and Ameliorated by Immune-Modifying Nanoparticle Therapy. Invest Ophthalmol Vis Sci 58:282-291
van der Gracht, Esmé; Zahner, Sonja; Kronenberg, Mitchell (2016) When Insult Is Added to Injury: Cross Talk between ILCs and Intestinal Epithelium in IBD. Mediators Inflamm 2016:9765238
Krause, Petra; Zahner, Sonja P; Kim, Gisen et al. (2014) The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice. Gastroenterology 146:1752-62.e4
del Rio, Maria-Luisa; Fernandez-Renedo, Carlos; Scheu, Stefanie et al. (2014) Therapeutic blockade of LIGHT interaction with herpesvirus entry mediator and lymphotoxin ? receptor attenuates in vivo cytotoxic allogeneic responses. Transplantation 98:1165-74
Shui, Jr-Wen; Kronenberg, Mitchell (2014) HVEM is a TNF Receptor with Multiple Regulatory Roles in the Mucosal Immune System. Immune Netw 14:67-72
Steinberg, Marcos W; Huang, Yujun; Wang-Zhu, Yiran et al. (2013) BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection. PLoS One 8:e77992
Shui, Jr-Wen; Kronenberg, Mitchell (2013) HVEM: An unusual TNF receptor family member important for mucosal innate immune responses to microbes. Gut Microbes 4:146-51
Shui, Jr-Wen; Larange, Alexandre; Kim, Gisen et al. (2012) HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488:222-5

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