Defining the immune regulatory function of LIGHT specific LTβR interactions in mucosal tissue. (MUC5P.747)

Inflammatory bowel disease is characterized by an exacerbated inflammation of the intestine. While blocking tumor necrosis factor α (TNFα) helps many patients, it also causes significant side effects including a hampered host defense. TNFSF14/LIGHT, another member of the TNF superfamily, can bind to two receptors, HVEM and lymphotoxin β receptor (LTβR). Though LIGHT expression by T cells has been described to be inflammatory, we have recently shown that LIGHT interaction with LTβR is protective in murine colitis, indicating therapeutic promise for LIGHT. In absence of LIGHT-LTβR interactions, the innate immune system prolongs and exacerbates intestinal inflammation, with increased IL-1β and oncostatin M expression leading to increased IL-6. To define the cell-cell interactions leading to the excessive inflammation, we have analyzed mice with a conditional deletion of the LTβR. A dendritic cell-specific lack of the LTβR caused aggravated colitis compared to wild type but less severe colitis than in LIGHT-deficient mice. Thus, other LTβR-expressing cell types may be involved. To identify the cell types involved in the protective LIGHT-LTβR interaction in mouse colitis, we generated conditional mutants of LIGHT and are currently analyzing these mice. Intriguingly, mice lacking lymphotoxin β (LTβ), a subunit of the other ligand for the LTβR, were protected from severe disease. These data suggest that there are antagonistic effects of LIGHT and LTβ engagement of the LTβR.