Introduction
Mucosal-associated invariant T (MAIT) cells are a specialized subset of innate-like T lymphocytes that are highly enriched in the human liver, positioning them as key immunological players at the interface between host defense and tissue homeostasis. These cells recognize microbial vitamin B metabolites presented by MR1 and rapidly respond by producing cytokines and cytotoxic mediators. In the liver, MAIT cells are uniquely adapted to sense environmental and metabolic changes, enabling them to participate in antimicrobial immunity, inflammatory amplification, and tissue repair. However, chronic liver diseases profoundly reshape the MAIT cell compartment, altering both their frequency and function. Understanding how MAIT cells adapt to diverse pathogenic contexts is critical for deciphering their dual roles in liver protection and disease progression.
Phenotypic and Functional Characteristics of Hepatic MAIT Cells
Hepatic MAIT cells display a distinct phenotypic profile characterized by high expression of CD161, semi-invariant TCRs, and tissue-residency markers, reflecting their adaptation to the liver microenvironment. Functionally, these cells rapidly secrete pro-inflammatory cytokines such as IFN-γ and TNF-α, as well as IL-17 under specific conditions, while also exhibiting cytotoxic potential through granzyme and perforin release. Beyond immune defense, MAIT cells can contribute to tissue repair by producing growth factors and regulatory mediators. Their functional plasticity allows them to shift between protective and pathogenic roles depending on local inflammatory, metabolic, and microbial signals.
MAIT Cell Dysregulation in Viral and Metabolic Liver Diseases
In chronic viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), MAIT cells undergo marked numerical depletion and functional exhaustion. Persistent antigen exposure, inflammatory cytokines, and metabolic stress drive phenotypic alterations, including reduced cytokine responsiveness and impaired antimicrobial activity. Despite their reduced numbers, residual MAIT cells may retain inflammatory potential, contributing to ongoing liver injury. Comparative analyses suggest that while viral and metabolic etiologies differ in their primary triggers, both converge on shared pathways of MAIT cell dysfunction linked to chronic inflammation and immune exhaustion.
Role of MAIT Cells in Alcohol-Associated and Cholestatic Liver Diseases
Alcohol-associated liver disease and biliary tract disorders exert distinct yet overlapping effects on MAIT cell biology. Alcohol-induced gut barrier disruption increases microbial translocation, leading to chronic MAIT cell activation and subsequent functional impairment. In cholestatic and biliary diseases, altered bile acid composition and persistent epithelial stress influence MAIT cell localization and activation status. In these settings, MAIT cells may amplify inflammatory cascades and interact with other immune and non-immune cells, contributing to fibrosis and disease progression while simultaneously attempting to preserve antimicrobial surveillance.
MAIT Cells in Autoimmune Hepatitis and Hepatocellular Carcinoma
Autoimmune hepatitis and hepatocellular carcinoma (HCC) represent immune-mediated and malignant contexts in which MAIT cell functions are further reprogrammed. In autoimmune hepatitis, MAIT cells may enhance immune-mediated hepatocyte damage through pro-inflammatory cytokine production and cytotoxicity. In contrast, within the tumor microenvironment of HCC, MAIT cells often exhibit profound dysfunction, with reduced effector capacity and altered spatial distribution. These changes highlight the complex interplay between immune surveillance, chronic inflammation, and immune evasion in shaping MAIT cell responses.
Spatially Anchored Frameworks for Studying MAIT Cells in Liver Disease
Emerging spatial and single-cell technologies provide new opportunities to study MAIT cell biology within the architectural and cellular complexity of the liver. Spatial transcriptomics, multiplex imaging, and advanced in situ profiling can reveal how MAIT cell function is influenced by their precise localization within hepatic niches. Integrating these approaches with functional and clinical data offers a conceptual framework to better understand how microenvironmental cues dictate MAIT cell behavior across disease stages. Such spatially anchored analyses may ultimately inform targeted therapeutic strategies aimed at modulating MAIT cell responses in chronic liver disease.
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