DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

Abstract

Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1–mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B–mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.

Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy

“…Similar to other CD8 + T cells and Tconvs, Tregs express other ICRs in the TIME (Wing et al, 2008;Sakuishi et al, 2013;Kurtulus et al, 2015). In Tregs, other ICRs (e.g., CTLA4, TIGIT, and TIM3) are responsible for maintaining the stability and functionality of TI Tregs (Wing et al, 2008;Sakuishi et al, 2013;Kurtulus et al, 2015;Sato et al, 2021). Therefore, there is a possibility that other ICRs still act on the maintenance of Treg stability and functionality in PD-1-blocked TI Tregs, thereby inducing resistance to PD-1 therapy.…”

Deletion of CD226 in Foxp3+ T cells Reduces Diabetes Incidence in Non-Obese Diabetic Mice by Improving Regulatory T Cell Stability and Function

“…In contrast, surface expression of TIGIT was increased in ex-Tregs compared to early Tregs (1.5-fold; p=0.0194) and naïve Tregs (1.4-fold; p<0.0001), but was comparable to EM Tregs (p=0.1576) (Figure1C-D). In addition to the studies demonstrating the role of CD226 in disrupting FOXP3 expression(16) while TIGIT restores Treg suppression(25), this data suggests that an imbalance of CD226:TIGIT signaling might play a role in ex-Treg development, contributing to the loss of Foxp3 expression in EM Tregs and promoting the proliferation of ex-Tregs.…”

“…recently identified CD226 signaling as a potential source of Treg instability, finding that pretreatment of human peripheral blood mononuclear cells (PBMCs) with an α-human CD226 blocking antibody diminished graft versus host disease (GvHD) development in a humanized mouse model by increasing human CD4 + FOXP3 + Treg numbers and upregulating their FOXP3 expression (16).…”

Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy

“…3) Direct inhibition of NK cell cytotoxicity and cytokine release ( 37 ). 4) The lack of CD226 can enhance the TIGIT/CD155 signal in the inflammatory environment, thereby inhibiting the AKT-mTORC1 pathway, stabilizing Foxp3 and maintaining the immunosuppressive function of Treg cells ( 38 ). Currently, CD155/TIGIT has shown potential targeted therapeutic effects in a variety of malignancies, such as high-grade serous ovarian cancer ( 39 ) and head and neck squamous cell carcinoma ( 40 ).…”

“…Besides, highly infiltrated TIGIT+ Treg cells and high levels of CD155 jointly mediate the enhanced inhibitory function of Treg cells in the tumor microenvironment of melanoma ( 61 ). The co-stimulatory receptor CD226 competes with TIGIT, and the deletion of CD226 can also enhance Treg cell function mediated by TIGIT ( 38 ).…”