TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

Abstract

T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed that Tigit expression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.

DW2008S and its major constituents from Justicia procumbens exert anti‐asthmatic effect via multitargeting activity

“…Furthermore, DW2008S and its two major constituents significantly reduced TIGIT expression in both concanavalin A‐activated spleen cells and polarized Th2 cells isolated from CD4 + T cells. Consistent with the results of a previous study, which showed increased TIGIT expression in the MLNs of mice with Th2‐driven allergic asthma,16 we observed that TIGIT expression was elevated in the MLNs of mice with allergic asthma. However, TIGIT expression was restored to its normal level by DW2008S.…”

“…In addition, TIGIT stimulates Th2 cell differentiation through its interaction with CD155 to promote the development of allergic disease 16. Therefore, we investigated whether TIGIT is involved in selective regulation of Th2 responses.…”

“…To elucidate whether the selective inhibitory effects of DW2008S on Th2‐driven inflammation arise from TIGIT + Th2 cell regulation or TIGIT + Treg regulation, we evaluated the numbers of subsets of MLN TIGIT + CD4 + T cells from mice with allergic airway inflammation 16. The total number of MLN TIGIT + CD4 + T cells was significantly higher in the OVA asthma group than in the Normal group; however, it was normalized after DW2008S was administered to the animals (Figure 4A, B).…”

“…Recent studies have provided evidence that TIGIT is an important factor in Th2‐driven responses and Th1/Th2/Th17 cell balance 16, 25. However, no regulators of TIGIT, except for a few specific antibodies, have been identified or developed.…”

“…Recently, TIGIT + Tregs have been shown to selectively suppress Th1 and Th17 responses but not Th2 responses 15. Moreover, TIGIT improves Th2 responses and allergic disease through the activity of CD155, whereas blockade of TIGIT with a neutralizing anti‐TIGIT antibody exerts a therapeutic effect on allergic airway inflammation in a murine model of asthma 16. However, there is still no chemical agent or herbal medicine that can selectively regulate Th2‐driven allergic inflammation via TIGIT regulation.…”