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

摘要

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.