ROLE OF THE SURFACE PROTEIN TIGIT IN CNS IMMUNOLOGY

F.A. Manzoli^1* and S. Turroni²

¹ Regional Health Service of Emilia-Romagna, Rizzoli Orthopedic Institute, Bologna, Italy.
² Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

*Correspondence to:
Prof. Francesco Antonio Manzoli,
Regional Health Service of Emilia-Romagna,
Rizzoli Orthopedic Institute,
40136 Bologna, Italy.
e-mail: dirscien@ior.it

Received: 14 January, 2026 Accepted: 09 March, 2026

ISSN 2279-5855 print / 2974-6345 [online] Copyright 2026 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Immunoreceptor tyrosine-based inhibitory motif (TIGIT) is an inhibitory immune receptor expressed primarily on Treg lymphocytes, CD4⁺ and CD8⁺ lymphocytes, and natural killer (NK) cells. Activation of these immune cells leads to increased TIGIT expression which can occur in pathological states such as chronic infections and tumors. TIGIT binds to the ligands CD155 and CD112 expressed on various cells such as dendritic cells, epithelial cells, macrophages, and tumor cells, exerting its inhibitory function. When TIGIT binds to CD226 or DNAX Accessory Molecule-1 (DNAM-1), it deactivates it by competing with it. If TIGIT is blocked with monoclonal antibodies, the immune response, particularly that of T cells, is restored. Intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) plays an important role in the nervous system where its activation mediates inhibitory signals, especially at the immune level, where immune cells such as microglia express ITIM. ITIM participates in synaptic regulation and neuronal activity and is altered in diseases such as Alzheimer’s disease and Parkinson’s disease. TIGIT binds to CD155/CD112 and activates the phosphorylation of the ITIM motif, recruiting SHP-1/SHP-2 phosphatases and inhibiting TCR signalling and inflammation. When the TIGIT receptor binds to its external ligands, the intracellular ITIM domain is phosphorylated, resulting in intracellular inhibition of T lymphocytes, microglia, and cytotoxic cells. Activation of ITIM recruits inhibitory proteins (phosphatases) and blocks activating signaling pathways. In other words, TIGIT uses the ITIM to suppress the immune response.

KEYWORDS: Immunoreceptor tyrosine-based inhibitory motif, TIGIT, ITIM, receptor, CNS, immunology

INTRODUCTION

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a receptor on the surface of T lymphocytes that acts as an off switch for the immune system (1). Inhibiting T-lymphocyte activation via CTLA-4 can prevent autoimmune reactions and maintain homeostasis, while deactivating CTLA-4 can enhance the immune response in tumors, as it is suppressed in these cases (2).  Immunoreceptor tyrosine-based inhibitory motif (TIGIT) is an inhibitory receptor expressed primarily on T lymphocytes that plays a key role in regulating the immune response and is particularly studied in immunology and oncology (3). CTLA-4 and TIGIT are both immune checkpoints that participate in the negative regulation of the immune response, especially in T lymphocytes and in contexts of autoimmunity and neuroinflammation, and act through complementary and synergistic mechanisms (2).

The T-cell immune receptor with Ig and intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) domains is expressed on regulatory T cells (Tregs), CD4⁺ and CD8⁺ lymphocytes, and natural killer (NK) cells. CTLA-4 and TIGIT are two inhibitory immune checkpoints that regulate T-cell activation and immune tolerance (4). The molecular structure of CTLA-4 and TIGIT differs in that CTLA-4 possesses an intracytoplasmic tyrosine inhibitory motif, while TIGIT possesses a motif involving ITIM and ITT-like motifs (5). They are both surface receptors that transmit inhibitory signals by binding to ligands. TIGIT expression increases when CD4⁺ T cells are activated or during chronic stimulation caused by chronic infections or tumors (6). TIGIT primarily uses the ligands CD155 and CD112, which are expressed on dendritic cells, epithelial cells, macrophages, and tumor cells, but can also bind and disactivate CD226 (activator), also known as DNAX Accessory Molecule-1 (DNAM-1), a surface glycoprotein expressed on various immune cells, including T lymphocytes.  (7). TIGIT has a higher affinity for CD155, competing with CD226, and blocks the activation signal (8). The TIGIT receptor binds to CD155 and, through its cytoplasmic domain, transmits inhibitory signals to the immune and inflammatory systems.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

TIGIT is a checkpoint inhibitor and has a cytoplasmic domain that allows it to signal intracellularly (9,10). TIGIT acts as an inhibitory receptor of the immune system and mediates inflammation (11,12). TIGIT binds to its ligand CD155 and inhibits the T-cell response involved in the destruction of tumor cells. Inactivating and blocking TIGIT with monoclonal antibodies restores the T-cell immune response (13). The use of TIGIT inhibitors in combination with PD-1 inhibitors can restore the T-cell response in acquired T-cell immune deficiencies (14-16). This novel approach could be used alone or in combination with other immunostimulatory drugs.

ITIM is a protein with a specific amino acid sequence containing tyrosine present in the cytoplasmic portion of some membrane receptors and has important interactions with the nervous system (6,17,18). ITIM is present in the cytoplasmic tail of several inhibitory immune receptors, including TIGIT (19). ITIM is a regulator that, when activated, leads to intracellular inhibitory signals.

ITIMs are present in many inhibitory receptors of immune cells, such as NK cell receptors, FcγRIIB receptors of B lymphocytes, and some macrophage receptors (20). When the tyrosine is phosphorylated, the ITIM can recruit inhibitory enzymes. The reaction begins with the binding of the ligand to its receptor, and the tyrosine of the ITIM is phosphorylated by tyrosine kinase. The phosphorylated site subsequently recruits cytoplasmic phosphatases, especially SHP-1 and 2, and SHIP (21).

Reactive phosphatases suppress or attenuate cellular activation signals. These reactions lead to the inhibition of the cellular response, and primarily to preventing an excessive immune response, as occurs in autoimmune diseases (22). Microglia in the central nervous system (CNS) express ITIM, which controls neuroinflammation and regulates the immune response (23). ITIM domains may participate in synaptic regulation and modulation of intracellular signaling in neurons (24). Alterations of these pathways occur in many neurological diseases, including Alzheimer’s disease and Parkinson’s disease (17).  Ligand activation of the receptor causes phosphorylation of the ITIM/ITT motifs, recruitment of phosphatases such as SHIP1, and inhibition of the T cell receptor (25). These reactions lead to decreased levels of NK cell cytotoxicity, T cell proliferation, and production of pro-inflammatory cytokines. In dendritic cells, TIGIT binding to its receptor CD155 can induce the production of anti-inflammatory cytokines and inhibition of IL-12, promoting a low-grade immune response (26).

TIGIT acts through an important mechanism of negative regulation of the immune response and also plays a significant role in immunity and inflammation in the CNS (27).  Excessive immune system activity and neuroinflammation can damage neurons and glial cells, but many inhibitory receptors are activated when this occurs to contain immune cells and control the inflammation. The TIGIT ligands CD155 and CD112 can be expressed by CNS microglia, endothelial cells, and dendritic cells (28).  Activation of TIGIT through these ligands leads to a decrease in the production of pro-inflammatory cytokines such as IL-1, TNF, IL-6, and IFNg, and promotes the production of Treg cells and anti-inflammatory cytokines such as IL-10.  (29).  In some CNS diseases, TIGIT has been shown to be effective in protecting and reducing neuroinflammation.

TIGIT activates the phosphorylation of the ITIM motif to recruit phosphatases (SHP-1/SHP-2) and inhibit TCR signaling and inflammatory pathways (30). This leads to reduction of T cell activity in the CNS, control of neuroinflammation, and increased immune tolerance (31). In addition, TIGIT regulates T-cell activity in neuroinflammation, increasing Treg cell activity and reducing the production of pro-inflammatory cytokines. TIGIT helps limit excessive immune activation in many neurological diseases such as autoimmune encephalitis, Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.

Inflammation is mediated by immune cells such as dendritic cells, microglia, and CNS T lymphocytes (32). The TIGIT receptor with an extracellular Ig-like domain and the ITIM and ITT-like motif bind the ligands CD155 and CD112 (33). The binding of TIGIT to CD155 leads to phosphorylation of the ITIM domain, recruitment of phosphatases, and inhibition of PI3K/Akt and MAPK (34). Thus, TIGIT utilizes two competing ligands; CD155 is an inhibitor of immune activation, while CD226 is an activator. When CD155 predominates, IL-10 is activated and inflammation is reduced, while when CD226 predominates, pro-inflammatory cytokines are increased (26).

CONCLUSIONS

TIGIT is an inhibitory immune checkpoint that controls neuroinflammation but with effects that can also be contrasting, depending on the context. TIGIT could be useful in the treatment of autoimmune and neurodegenerative diseases, such as Alzheimer’s disease, where there is an excessive inflammatory response.

Conflict of interest

The authors declare that they have no conflict of interest.

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