Recent Advances in Understanding the Role of TIGIT plus Follicular Helper T Cells in IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by elevated serum IgG4 levels and massive infiltration of IgG4+plasma cells. Although storiform fibrosis, obliterative phlebitis and IgG4+plasma cell infiltration are well described pathological features in this disease, the excessive formation of tertiary lymphoid organs (TLOs), particularly in the early phase of the disease lesions, has gained much attention. TLOs of IgG4-RD are orchestrated by specific immune cell subsets including follicular helper T cells (Tfh), CD20+ B cells, and CD21+ follicular dendritic cells (FDCs). Tfh is the key player of this disease because recent studies have suggested the pathological role of this immune cell subset in formation of TLOs, helping IgG4+plasma cell differentiation, inducing storiform fibrosis by secreting interleukin-4, and activating cytotoxic T cells by secreting interleukin-21. We have recently identified a new Tfh subset which expresses T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). TIGIT+Tfh efficiently produces interleukin-21 through OX40 signal, and the increase in peripheral TIGIT+Tfh cells reflects disease activity in IgG4-RD. TIGIT is important to mediate the retention and positioning of TIGIT+Tfh within TLOs through interaction with CD155 expressed on CD21+ FDCs. In this review, we summarize and discuss recent progress in understanding the pathogenesis of IgG4-RD, focusing on TIGIT+Tfh.