TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

Abstract

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses

“…As such, our data provide an insight into the formation of these highly pathogenic cells in vivo, and suggest that targeting of inflammatory monocytes could lead not only to a decrease in the production of proinflammatory cytokines, but also in a reduction in Th17 cells. Recent literature indicates that, in addition to multiple cytokine signals, cell-derived factors may be required for the generation or expansion of Th17 cells (2,27,28). We show that in vitro activated monocytes from both HC and RA patients induce Th17 responses in an IL-1␤/TNF-␣-dependent fashion.…”

Death receptor 3 is essential for generating optimal protective CD41 T‐cell immunity against Salmonella

“…In vitro, CD4 1 T cells that cannot signal via DR3 are defective in the secretion of a number of cytokines including IL-2, IL-4, IL-5, IL-13, IL-10, IL-17, but not IFN-g [5,14]. Furthermore, addition of TL1A enhanced the proliferation of in vitro generated Th17 cells upon re-stimulation, but had no effect on the proliferation of Th1 cells [13]. Consistent with these findings transgenic mice that constitutively express TL1A have increased levels of IL-13 and IL-17 but not IFN-g under steady-state conditions [15,16].…”

“…Studies using TL1A À/À or DR3 À/À mice have revealed a role for TL1A/DR3 in exacerbating Th2-and Th17-cell-dependent inflammatory and autoimmune conditions [5,13]. In contrast, no studies have reported a role for DR3 in host immune responses to infection.…”

“…Unlike TNFR1 however, which is widely expressed, expression of DR3 is limited primarily to T cells, cells of the monocyte/macrophage lineage and lymphoid tissue inducer (LTi) cells [8][9][10]. DR3 interacts with TL1A (TNFSF15), a TNF-like protein that is expressed on activated macrophages, dendritic cells, T cells and endothelial cells and is produced either as a membrane-anchored protein or a soluble cytokine [5,11,12].Studies using TL1A À/À or DR3 À/À mice have revealed a role for TL1A/DR3 in exacerbating Th2-and Th17-cell-dependent inflammatory and autoimmune conditions [5,13]. In contrast, no studies have reported a role for DR3 in host immune responses to infection.…”

DETERMINATION OF LEVEL EXPRESSION OF mRNA SPLICING VARIANTS FOR DR3 IN BLOOD CELLS IN INFECTIOUS MONONUCLEOSIS

“…DR3 экспрессируется преимущественно в се-лезенке, тимусе и лейкоцитах периферической крови (T-и В-лимфоцитах, NK-и NKT-клетках, макрофагах) [8]. Описана важная роль данного рецептора как в регуляции иммунных реакций, так и в развитии воспалительных, аутоиммунных, онкологических и инфекционных заболеваний [5,7,9,10].…”