Galectin 9: Role in T-Cell Regulation and Autoimmunity

Galectin-9 is a carbohydrate-binding protein that plays a crucial role in immune regulation, particularly in modulating T-cell responses. Its interactions with immune checkpoints influence inflammation, tolerance, and exhaustion, making it a key factor in both protective immunity and disease progression.

Understanding how Galectin-9 shapes T-cell function provides insight into its potential as a therapeutic target for conditions ranging from chronic infections to autoimmune diseases.

Molecular Characteristics

Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains (CRDs) connected by a flexible linker. These CRDs bind β-galactoside-containing glycans, dictating interactions with glycoproteins on the cell surface and in the extracellular matrix. The affinity and specificity of Galectin-9 for different glycans are influenced by post-translational modifications, such as glycosylation patterns on target proteins, which modulate its biological activity. Variations in glycan presentation across tissues and disease states further shape its function.

Its structural flexibility allows Galectin-9 to crosslink glycoproteins and form lattice-like structures on the cell membrane, enhancing receptor clustering and downstream signaling. The linker region affects its stability and binding kinetics, with isoforms differing in linker length and biological effects. Alternative splicing generates multiple isoforms with distinct functions, contributing to tissue-specific regulation.

Beyond its extracellular role, Galectin-9 is found in the cytoplasm and nucleus, where it interacts with intracellular proteins to influence gene expression and RNA splicing. Its nuclear localization signals enable shuttling between compartments, affecting protein-protein interactions and intracellular signaling. The balance between its extracellular and intracellular functions is dictated by cellular context, post-translational modifications, and environmental cues.

Binding Mechanisms With PD-1 And TIM-3

Galectin-9 regulates immune responses through direct interactions with checkpoint molecules PD-1 and TIM-3. These interactions depend on its CRDs binding to glycosylated residues on these receptors. The glycosylation status of PD-1 and TIM-3 determines the strength and specificity of Galectin-9 binding, influencing receptor clustering and downstream signaling.

The interaction with TIM-3 has been well studied due to its role in stabilizing TIM-3’s engagement with phosphatidylserine on apoptotic cells. Galectin-9 enhances TIM-3 signaling by promoting receptor oligomerization, amplifying inhibitory pathways. Structural analyses reveal that Galectin-9 binds N-linked glycans on TIM-3’s IgV domain, facilitating recruitment of signaling molecules and reinforcing TIM-3-mediated inhibition. Since TIM-3 is highly glycosylated, variations in glycan structures across cell types influence the functional consequences of Galectin-9 binding.

Similarly, Galectin-9 interacts with PD-1, a receptor known for its inhibitory role in immune signaling. While PD-1’s glycosylation is less characterized, emerging studies suggest Galectin-9 preferentially binds specific N-glycans on its extracellular domain. This interaction may alter PD-1 receptor dynamics, affecting its engagement with PD-L1 or PD-L2. Some evidence suggests Galectin-9 promotes PD-1 clustering, enhancing inhibitory signaling, while other studies indicate it may compete with conventional ligands, modifying PD-1’s accessibility. The precise functional consequences remain an area of active investigation.

Effect On T-Cell Exhaustion

Persistent antigen exposure in chronic infections and malignancies drives T-cell exhaustion, marked by functional decline and sustained expression of inhibitory receptors. Galectin-9 influences this process through its interactions with glycosylated checkpoint receptors, affecting receptor clustering and signaling intensity.

In tumor microenvironments and chronic inflammation, elevated Galectin-9 levels correlate with increased exhaustion markers like PD-1, TIM-3, and LAG-3. High Galectin-9 concentrations coincide with reduced cytokine production and impaired T-cell proliferation, reinforcing the exhausted phenotype. Experimental models show that blocking Galectin-9 can partially restore T-cell function, suggesting its role in maintaining exhaustion. The severity of its effects depends on concentration and receptor glycosylation patterns, which vary across disease contexts.

Beyond maintaining exhaustion, Galectin-9 may contribute to epigenetic reprogramming of exhausted T cells. Persistent exposure has been linked to chromatin modifications that reinforce exhaustion-associated transcription, making functional recovery more challenging. Transcriptomic and epigenetic studies indicate Galectin-9 upregulates transcription factors like TOX and NR4A, central to exhaustion programming, extending its influence beyond receptor engagement.

Roles In Autoimmune Disorders

Dysregulated immune tolerance is a hallmark of autoimmune diseases, and Galectin-9 plays a role in balancing pathogenic and regulatory immune processes in conditions such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA). Its expression levels fluctuate in these diseases, often correlating with severity, suggesting it can either exacerbate or mitigate pathology depending on context.

In SLE, elevated Galectin-9 levels in serum and affected tissues influence immune cell infiltration and inflammatory cascades. Some studies suggest Galectin-9 sustains chronic immune activation by interacting with autoreactive lymphocytes, while others highlight its role in promoting regulatory T-cell expansion, making it a potential biomarker for disease remission or therapeutic response. In MS, Galectin-9 modulates neuroinflammation by interacting with microglia and infiltrating T cells, affecting the balance between inflammatory and reparative responses in the central nervous system.