Mononuclear phagocytes in the lamina propria of mouse and human intestine are capable to express TL1A. Macrophages overexpressing TL1A promoted secretion of TNF-α and IL-1β (26). Monocytes secreted TL1A in response to stimulation by immune complexes, leading to enhanced T cell responses (5, 27). In inflammatory bowel disease, TL1A is produced in the intestinal lamina propria of macrophages in patients with Crohn’s disease (23).

TL1A activated DCs and promoted migration of DCs, thereby exacerbating development of inflammatory diseases (28). The receptor for TL1A, DcR3, is able to directly regulate DCs differentiation and maturation, and then modulates T cells differentiation and function (29). TL1A binding to DR3 synergies with IL-12 and IL-18 to increase interferon-γ (IFN-γ) production in natural killer cells (NK cells) (30). TL1A enhances NK cells infiltration and anti-tumor response as well as NK cells cytotoxicity to target cells (31, 32). In the antigen-induced arthritis (AIA) mice model, DR3 treatment increased neutrophils proliferation, and released much neutrophil chemokine (C-X-C motif) Ligand 1 Protein (CXCL1), gelatinase matrix metalloproteinase 9 (MMP-9), driving early cartilage destruction (33).

As regulators of innate immunity, innate lymphoid cells (ILCs) have been shown to play a key role in mucosal homeostasis and inflammatory diseases. High DR3 expression was found in both human and mice ILCs, which increases cytokine production such as IL-25, IL-33 in response to TL1A stimulation (34, 35). Role of type 2 cells (ILC2) is dependent on the TL1A/DR3 axis, which promotes expansion, survival and function of ILC2 (34). TL1A and DR3 co-stimulates IL-5 and IL-13 production by ILC2, driving allergic pathology and participating in development of allergic lung inflammation (36). ILC3 regulates intestinal immunity, while activation of DR3 signaling pathway leads to ILC3 loss and promotes intestinal inflammation (37). TL1A can synergy with IL-23 and IL-1β to increase ILC3 proliferation and produce cytokines such as IL-22 and granulocyte macrophage colony stimulating factor (GM-CSF), suggesting a central role for TL1A in promoting the ILC3 immune barrier (38, 39). Collectively, TL1A binds to receptors and then regulates innate immune response ( Figure 2 ).

TL1A synergies with IL-12 and IL-18 to induce secretion of IFN-γ and TNF-α, thereby boosting helper T cell 1 (Th1) immune response (30, 40). However, function of TL1A in the adaptive immune system is not limited to Th1 immune response. TL1A activated T cells, promoting IL-5 and IL-13 production in the intestinal mucosa, which are characteristic cytokines produced by helper T cell 2 (Th2) cells (30, 41). Blocking TL1A disrupted IL-13 secretion, suggesting that TL1A is critical in Th2 immune response (19). Interestingly, role of TL1A in helper T cell 17 (Th17) response appears dichotomous. TL1A has been reported to inhibit generation and polarization of Th17 cells in mice and human CD4+ T cells by binding to DR3 (42). By contrast, some studies showed that TL1A could augment Th17 differentiation through up-regulation of (retinoic acid-related orphan nuclear receptor C (RORc) expression (a Th17 lineage-specific transcription factor) and induce the proliferation of Th17 cells upon DR3 activation (8, 42, 43). The evidence indicated that TL1A aggravates inflammatory reactions through regulating Th17 pathway. It is known that TL1A also regulates generation of Th9 cells that are involved in the pathogenesis of IBD and allergic lung inflammatory disease (44, 45). TL1A up-regulated transforming growth factor-β (TGF-β) and IL-4 expression to stimulate Th9 differentiation and IL-9 secretion (44, 46). TL1A mediates Th9 differentiation through an IL-2 and STAT5-dependent mechanism ( Figure 2 ) (45).

Compared to wild-type (WT) mice, a population of CD4+ T cells expressing IFN-γ was significantly decreased in TL1A gene deficient mice, while activation of the TL1A/DR3 pathway resulted in higher levels of Th1 cytokine production in SAMP1/YitFc (SAMP) mice and mitigated anti-inflammatory process during Chronic Ileitis (35, 42). Transgenic mice that were constitutively expressed TL1A in T cells or DCs, significantly developed IL-13-dependent inflammatory intestinal pathology, suggesting that TL1A is involved in the Th2 immune regulation (47). In transgenic mice with overexpression of TL1A, as well as in UC patients, there was enhanced Th9 cell differentiation, IL-9, TGF-β, and IL-4 expression (38). Similarly, in allergic lung disease mice model, binding of TL1A to DR3 could enhance differentiation and pathogenicity of Th9 cells. Exogenous TL1A suppresses the differentiation of naïve CD4+ T cells into Th17 cells, which is independent of STAT1 signaling and IL-2 signaling (48). TL1A, alone or in combination with IL-23, stimulated peripheral blood mononuclear cells (PBMCs) to produce IL-17 in autoimmune diseases, such as psoriasis vulgaris (PV) (49, 50), systemic sclerosis (SSc) (51), IBD (52). TL1A induced high levels of IL-22 in memory CD4+ T cells and committed Th17 cells through secretion of IL-9 (53). Moreover, DCs lacking TL1A had a reduced ability to induce Th17 differentiation and proliferation in experimental autoimmune encephalomyelitis (EAE) (26), and anti-TNF-α treatment inhibited effects of TL1A-mediated Th17 differentiation in RA (43).

Regulatory T cells (Treg) are a subset of CD4+ T cells, and maintain effector cells activation and proliferation. Activation of the TL1A/DR3 axis leads to Treg cells expansion and activation, and controls exuberant immune activation ( Figure 2 ) (47, 54, 55). However, some studies showed that triggering DR3 in conventional effector CD4+ T cells and Treg cells enables TL1A to directly or indirectly attenuate the suppressive function of Treg cells (56). These inconsistent findings may suggest that the effect of TL1A on Treg cells might be highly dependent on the immune response environment regulated in vivo or in vitro (13, 57). However, more studies are needed to better clarify exact role of TL1A/DR3 in Treg cells.

Compared with T cells, there is limited evidence discussed effects of TL1A on B cells. A study revealed that plasma cells are the direct targets of TL1A, and TL1A promotes plasma cells survival and different antibodies production, which in turn enhance pathogenic antibodies production in CIA (collagen induced arthritis) mice (58). TL1A inhibits B cell proliferation and helps effector B cells to maintain immune homeostasis (59).

Therefore, TL1A is a pivotal mediator in adaptive immunity, including T and B cells.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by erosive arthritis. The main pathological features of RA are joint synovial hyperplasia, formation of pannus, bone destruction, and joint dysfunction (60). FLSs are major component of hyperplastic synovial tissue and involve in the inflammatory process and pathogenesis of RA (61). TL1A enhanced differentiation of Th17 cells induced by IL-6 and TGF-β stimulation through activation of RORc. The cytokine IL-17 produced by Th17 can prolong the survival of RA-FLSs and germinal center immune cells. FLSs then trigger cartilage degradation by producing inflammatory factors and matrix degradation molecules, damaging the joint and ultimately leading to RA (43, 60).

CIA is a model of human RA with similar histopathological and clinical features (62). After treatment with anti-TL1A antibody, total joint score was decreased and clinical inflammation of CIA mice was effectively alleviated, which was mediated by blocking the TL1A/DR3 signaling pathways (63). Similarly, compared to WT mice, TL1A gene knockout mice had improved clinical profiles for CIA (improved synovial hyperplasia and cartilage erosion) through reduction of inflammatory cells infiltration and reduced production of pathogenic antigens (58). In vitro experiments showed that in the presence of Receptor Activator of Nuclear Factor-κ B Ligand (RANK-L) and macrophage colony-stimulating factor (M-CSF), DR3-dependent TL1A promoted osteoclast formation in RA patients and mice model, suggesting that TL1A drives the bone pathology of RA (64).

TL1A levels in serum and synovial fluid were higher in RA patients when compared to that in healthy controls and correlated with expression of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), as well as disease activity ( Table 1 ) (63, 68, 69). RF and anti-CCP antibodies are promising disease markers for early diagnosis and prognosis of RA (63). Regarding genomics for TL1A gene, association of TL1A gene single-nucleotide polymorphism (SNP) (rs3810936 and rs7848647) with susceptibility to RA was discussed in Chinese population. TC, TT+TC genotypes of rs3810936, rs7848647 were negatively correlated with RA risk ( Table 2 ). The CC genotype of TL1A rs7848647 polymorphism contributes to elevated TL1A levels and is associated with antibody production (RF expression) (65). Expression of genes related to proliferation of RA-FLSs, including spectrin repeat-containing nuclear envelope 1 (SYNE1), Fc receptor-like 2 (FCRL2), PYD (pyrin domain)-containing 1 (PYDC1), cell division cycle 45 homolog (CDC45), signal transducer and activator of transcription 5B (STAT5B), and interferon regulatory factor 4 (IRF4), was increased after TL1A stimulation (70). The progressive course of RA implicates several systems damage, especially the cardiovascular system. Atherosclerosis is the most common complication in RA patients (71). A study found that elevated serum levels of TL1A in RA patients were significantly associated with progression of atherosclerotic plaque height, which may increase the risk of atherosclerosis in RA patients (75).

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic inflammatory intestinal diseases, and the pathogenesis was associated with susceptible genes, dysregulated immune system, and environmental factors (76).

TL1A affects epithelial to mesenchymal transition (EMT) in IBD patients via the TGF-β/Smad3 pathway, causing colonic fibrosis and inflammatory responses (77). TL1A is capable of increasing the barrier permeability of TNF-α-induced Caco-2 cell and reducing function of tight junction protein (TJ) through myosin light chain kinase/p-myosin II regulatory light chain (MLCK/p-MLC) pathway and LPS-mediated myeloid differentiation factor 88/TNF receptor-associated factor-6 (MyD88/TRAF6) pathway, which further damage the intestinal mucosal barrier (78, 79). TL1A induces expression of pro-inflammatory cytokines such as TNF-α to regulate intestinal microenvironment and aggravates intestinal inflammation (40). For instance, dextran sodium sulfate (DSS)-induced colitis mice with TL1A overexpression had more severe intestinal inflammation and bacterial translocation, suggesting that TL1A promotes intestinal mucosal barrier disruption (80).

TL1A expression was elevated in colonic tissues of IBD patients compared to healthy controls and correlated with severity of inflammation, especially in CD patients ( Table 1 ) (23, 77). The IBD protective allele A (rs6478109) was associated with increased tnfsf15 gene expression, indicating that IBD genetic susceptibility may relate to changes in TL1A expression (81). Rs10114470 polymorphism is considered to be a loci for IBD susceptibility in Chinese Han population ( Table 2 ) (80). Furthermore, TL1A gene rs6478109 polymorphism is an independent factor of surgery, which affects the long-term efficacy of anti-TNF antibody therapy (72). Interestingly, anti-TL1A drug (PF-06480605) improved tissue inflammation and inhibited expression of fibrotic pathways, and reduced intestinal pathogens in UC patients (82). To date, this drug underwent preclinical safety and tolerability testing and is expected to be used as a clinical trial drug for treatment of IBD-related diseases. However, further studies with PF-06480605 in patients with other inflammatory diseases are needed to confirm the effects and to clarify the mechanism in inhibiting the diseases (9, 66).

Psoriasis is a common inflammatory skin disease characterized by thickened, scaly, red skin patches (73). TL1A is predominantly expressed in psoriatic lesions, particularly in infiltrating inflammatory cells, keratinocytes and vascular cells (27, 74). TL1A promotes production of IL-17, which induces granulocyte colony-stimulating factor (G-CSF) and chemokine ligand 20 (CCL20) and recruits large number of neutrophils to damaged joints, leading to early inflammation. IL-17 also promotes osteoclast formation, causing local bone damage that may contribute to development of psoriatic arthritis (83). Imiquimod (IMQ)-induced elevated TL1A expression at lesions in psoriasis-like mice, and elevated TL1A exacerbated the psoriasis phenotype through increasing the number of T cells, neutrophils, and DCs, and upregulating inflammatory cytokines IL-17 and IFN-γ. After treatment with anti-TL1A antibody, the lesions were effectively alleviated and histopathological changes were significantly reduced, suggesting that TL1A is involved in the pathogenesis of psoriasis (49). TL1A can synergy with IL-23 to stimulate IL-17 secretion in PBMCs from psoriasis vulgaris patients, thereby aggravating the disease (50).

TL1A and DR3 protein levels, as well as mRNA expression, were much higher in patients with psoriasis than in healthy controls, and both of them were decreased after treatment ( Table 1 ) (50, 67). A study found that in Hungarians, TL1A gene rs6478109 polymorphism was associated with susceptibility to psoriasis. The haplotype AGTAA (rs3810936 (A)+rs6478108 (G)+rs6478109 (T)+rs7848647 (A)+rs7869487 (A) may have a protective effect in disease pathogenesis ( Table 2 ) (84). Collectively, TL1A may play a role in development of psoriasis.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease caused by biliary tract obstruction and cholestasis. TL1A is mainly expressed in biliary epithelial cells, vascular cells and infiltrating mononuclear cells of PBC liver (85). In mice model, TL1A may exacerbate liver fibrosis by recruiting macrophages and promoting secretion of pro-inflammatory cytokines (26). Compared with healthy controls, serum levels of TL1A were significantly elevated in PBC patients and decreased after ursodeoxycholic acid (UDCA) treatment ( Table 1 ). TL1A gene rs4979462 polymorphism was a PBC susceptible polymorphism in Japanese and Chinese Han population ( Table 2 ) (86, 87). The above results suggest that TL1A is associated with disease progression and may be involved in the pathogenesis of PBC.

TL1A has emerged as a key inflammatory mediator in different inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS). Studies indicated that expression of plasma TL1A was elevated in SLE patients and was positively correlated with disease activity score ( Table 1 ) (51). In a meta-analysis, the authors found that TL1A gene polymorphisms (rs3810936, rs7848647) may associate with SLE susceptibility ( Table 2 ) (88). There are few studies about TL1A and SLE, and more evidence is needed to elucidate the role of TL1A in SLE pathogenesis. In addition, TL1A expression was upregulated in AS patients ( Table 1 ) and TL1A gene rs3810936 TT genotype was associated with risk of AS in Chinese Han population ( Table 2 ) (89, 90).