TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses

Abstract

TNF-like ligand 1A (TL1A), also known as TNFSF15, is a member of the TNF superfamily. Its known receptor is death receptor 3 (DR3). In humans, TL1A also binds to a secreted TNF family member called decoy receptor 3, which interferes with the interaction between TL1A and DR3. TL1A/DR3 signal has been implicated in several autoimmune diseases in animal models as well as in clinical conditions. We generated TL1A gene knockout (KO) mice to assess its role in collagen-induced arthritis (CIA), a mouse model of human rheumatoid arthritis. The KO mice were fertile and had no visible anomalies. Their lymphoid organ size and cellularity, T and B cell subpopulations, Th cell and regulatory T cell development in vivo and in vitro, and antiviral immune responses were comparable to those of wild-type mice. However, the KO mice presented ameliorated CIA in terms of clinical scores, disease incidence, and pathological scores. The KO mice had reduced titers of pathogenic anti-collagen Abs in the sera. No apparent defect was found in the function of follicular Th cells. We revealed that plasma cells but not B cells expressed high levels of DR3 and were direct targets of TL1A. In the presence of TL1A, they survived better and produced more pathogenic Ab. This study presented novel knowledge about the role of TL1A in humoral immune responses and its mechanism of action in CIA pathogenesis.

CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss

“…Ablation of TL1A in a model of CIA has previously been demonstrated to partially block inflammation and focal bone erosion associated with the disease pathology [23]. The use of DR3 ko mice to investigate the pathogenesis of inflammation and focal bone erosion in CIA however, has never been carried out.…”

“…To address these shortcomings we utilized the murine model of CIA which shares many immunological and pathological similarities with RA: generation of autoantibodies toward self, breach of tolerance, symmetrical joint involvement, peripheral joints affected and systemic development of synovial hyperplasia, pannus formation and subsequent bone resorption [43], [44], [45]. In addition to DR3, TL1A, one of DR3’s two confirmed ligands, has also been demonstrated to contribute to the development and progression of focal bone erosions in murine models of inflammatory arthritis [23], while increased levels are observed in the serum and synovial fluid of patients with inflammatory arthritis [14]. These data highlight a significant role for DR3 in pathological bone loss however, the mechanism through which DR3 signalling acts upon bone-altering cells remains poorly defined.…”

“…The potentially important role for the DR3/TL1A pathway in regulating osteoclast (OC) formation and resorptive activity has been evidenced in murine and human studies. Cartilage damage and focal bone erosion were reduced or inhibited by DR3 or TL1A gene ablation in the murine models, antigen-induced arthritis (AIA) and collagen-induced arthritis [22], [23], [24]. Furthermore, addition of TL1A to human peripheral blood mononuclear cell (PBMC) cultures in the presence of macrophage colony stimulating factor (MCSF) and receptor activator of nuclear factor kappa B ligand (RANKL) enhanced OC formation [22].…”

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

“…DR3 (encoded by Tnfrsf25 ) is widely expressed in lymphoid and myeloid compartment including T cells, NKT cells (Fang et al, 2008; Pappu et al, 2008; Richard et al, 2015; Twohig et al, 2012), B cells (Cavallini et al, 2013; Wang et al, 2013), monocytes, alveolar macrophages (Facco et al, 2015) and innate lymphoid cells (ILC) type 2 and 3 (Meylan et al, 2014). DR3, a TNFR1 paralog similarly utilizes the death domain adaptor, TRADD to recruit TRAF2 and RIP kinase to form a signaling complex that activates the NF-κB and JNK pathway in T cells (Pobezinskaya et al, 2011).…”

“…In accordance, manifestation of symptoms in experimental autoimmune encephalomyelitis or allergic airway inflammation is ameliorated in Tnfrsf25 −/− mice (Meylan et al, 2008). Tnfsf15 −/− mice show disease severity in antigen-induced arthritis (Bull et al, 2008; Wang et al, 2013). DR3 activation either by agonistic antibody (4C12) (Schreiber et al, 2010), TL1A-Ig fusion protein (Khan et al, 2013), or TL1A transgenic mouse, induces Treg cell expansion.…”