Most immune cells, including over 95% of T cells, reside and function in tissues rather than in blood.¹ These tissues include lymphoid organs (e.g., bone marrow, spleen, and lymph nodes) and barrier surfaces (e.g., the skin, gut, and mucous membranes). Key populations of tissue-resident immune cells include tissue-resident memory T (T_RM) cells, dendritic cells, macrophages, and innate lymphoid cells, which are crucial for local immune responses.² T cells constitute an adaptive immune cell population that plays a central role in immune defense. Notably, CD8⁺ T cells eliminate infected, damaged, or tumor cells, while CD4⁺ T cells facilitate and regulate immune responses. The most important feature of the adaptive immune system is the formation of memory T cells, which enable a rapid and effective response upon re-exposure to pathogens. T_RM cells might serve this role immediately at the entry sites of various pathogens.³

The liver is a vital immunological organ, buffering gut contents and systemic circulation. About 80% of the liver’s blood supply comes from the gut via the portal vein. This blood is rich in dietary and microbial antigens, which must be processed by the liver as it performs immunosurveillance.⁴ Additionally, the liver has a distinctive anatomical vascular system, which allows continuous connection between immune cells, liver sinusoid endothelial cells (LSEC), and hepatocytes. Notably, its low-pressure blood flow and fenestrated endothelium facilitate interactions between immune cells and hepatic cells.⁵ The liver sinusoids and the space of Disse are populated by immune cells that maintain organ homeostasis and regulate inflammation. These cells adapt to this unique environment, adopting unique characteristics compared to the circulating population. For example, liver CD8⁺ T_RM cells exhibit special characteristics compared to circulating T cells, and play crucial roles in liver immunity, participating in both the initiation and resolution of intrahepatic inflammation. Dysregulation of T_RM cells is implicated in the pathogenesis of various liver diseases.⁶

In this review, we aim to provide valuable summaries for clinicians, such as gastroenterologists and hepatologists conducting clinical and translational research. We review the general features of CD8⁺ T_RM cells, with specific focus on the characteristics of liver T_RM cells. We will also compare liver T_RM cells between humans and mice, which supports the necessity of investigating this population using human samples. Finally, we will summarize the clinical implications of the present knowledge of liver T_RM cells in human liver diseases.

1. Phenotypic and transcriptional characteristics of T_RM cells

The term T_RM cells generally refers to conventional CD8⁺ memory (not naïve) T cells with αβ T cell receptor characterized by the expression of CD69 and/or CD103, which are not expressed in circulating T cells.⁷ CD69 and CD103 help T_RM cells reside in peripheral tissues, such as the epithelium, through interaction with molecules like E-cadherin and by inhibiting KLF2 and S1PR1, which facilitate egress from peripheral organs.⁸ T_RM cells also generally express CD49a and CXCR6,⁹ and lack markers typically found in central homing memory T cells, such as CCR7 and CD62L.¹⁰ One key transcription factor is Runx3, which is crucial for T_RM-cell differentiation.¹¹ Additionally, Hobit and Blimp are involved in driving T_RM-cell differentiation, and have been described as important transcriptional regulators.¹² Epigenetic modifications, like DNA methylation and histone acetylation, might also regulate T_RM-cell development and function. DNA methylation is reduced in key genes such as PRF1, CD39, and CD103, while histone acetylation support expressions of these genes in T_RM cells.^13,14 These findings indicate that T_RM cells have distinct phenotypic characteristics compared to circulating T cells (Fig. 1).

Figure 1. Schematic representation of circulating memory T cells and tissue-resident memory T (T_RM) cells. Circulating memory T cells lack CD69 and CD103; recirculate between the blood and secondary lymphoid organs. T_RM cells express CD69 and variably express CD103, CD49a, and CXCR6, enabling their retention in tissues, which is regulated by the downregulation of KLF2 and S1PR1. CXCR6, C-X-C chemokine receptor type 6; KLF2, Krüppel-like factor 2; S1PR1, sphingosine-1-phosphate receptor 1.

2. Generation and maintenance of T_RM cells

Multiple exposures to antigens can generate large pools of T_RM cells without altering the pre-existing T-cell pool, suggesting that antigen stimulation plays an important role in T_RM-cell generation.¹⁵ Some reports indicate that antigen stimulation is also required to maintain this population.¹⁶ Additionally, cytokines such as interleukin (IL)-15 have been considered critical for T_RM-cell differentiation and survival, through mechanisms involving mTOR signaling pathways.^17-20 Transforming growth factor (TGF)-β is also involved in converting circulating effector T cells into T_RM cells by enhancing the expressions of key surface receptors and transcription factors required for tissue residency.^17,21 Moreover, IL-33 can promote T_RM-cell survival and activation through the ST2 receptor.²² Hypoxia might also be linked to T_RM-cell generation and maintenance.¹⁵ Although several mechanisms reportedly support T_RM-cell maintenance, little is known about the longevity of human T_RM cells. Notably, studies in mice and rhesus macaques demonstrate that T_RM cells are stable for 300 to 700 days,^23,24 suggesting that they are capable of long-term stable survival.

3. Functional characteristics of T_RM cells

T_RM cells are located in various tissues—including the skin, lungs, salivary glands, intestines, and other mucosal sites—and can exist in both lymphoid and non-lymphoid tissues.²⁵ They are essential for conferring local immune protection against infections, and rapidly respond to pathogens without requiring recruitment from the bloodstream, thereby serving as an immediate defense line.²⁵ Upon encountering pathogens, T_RM cells can proliferate and secrete effector cytokines, such as interferon-γ (IFN-γ) and tumor necrosis factor (TNF), which control infections and recruit other immune cells to the infection site.^26,27 T_RM cells also contain cytotoxic molecules that can directly kill target cells.²⁸ In particular, T_RM cells play a significant role in defense against viral infections. For instance, influenza-specific T_RM cells in the lungs provide long-term protection by swiftly responding to re-infection and mounting a robust immune response.²⁹ T_RM cells also participate in defenses against bacterial and fungal infections. They can recognize and respond to these pathogens, ensuring rapid clearance and preventing widespread infection.³⁰ Importantly, T_RM cells adapt to the specific tissue environments they inhabit. For instance, lung T_RM cells are particularly adept at responding to respiratory pathogens, while skin T_RM cells are suited to handling cutaneous infections.^31,32 T_RM cells also significantly contribute to tumor surveillance and control. Higher T_RM-cell frequencies in tumors correlate with better patient outcomes, because these cells can produce effector cytokines and directly lyse tumor cells in various cancer types.³³ T_RM cells might also play a fundamental role in surveilling subclinical tumors and thereby maintaining cancer–immune equilibrium. A previous study in a mouse model demonstrated that T_RM cells within the epidermal layer of skin promoted a durable melanoma–immune equilibrium.³⁴ Skin T_RM cells played a crucial role in melanoma suppression, as evidenced by the findings that T_RM-cell generation was correlated with macroscopic tumor-free status, while T_RM-cell depletion led to tumor growth.

Although protective against infections, T_RM cells can also contribute to the pathology of autoimmune diseases. In conditions like psoriasis and vitiligo, T_RM cells drive inflammation and tissue damage through pro-inflammatory cytokine secretion.^27,35-37 The persistence of T_RM cells in affected tissues can promote chronic inflammation, exacerbating autoimmune conditions. Understanding these dual roles will help us to develop therapies that target pathogenic T_RM cells while preserving their protective functions. Notably, after organ transplantation, donor-derived T_RM cells can persist in grafts, and may either promote graft acceptance or contribute to rejection, depending on interactions between donor and recipient immune cells.^38,39 These findings suggest that T_RM cells might play dual roles in tissue protection and damage, which may vary depending on the clinical situation. In the following sections, we will review unique characteristics of liver T_RM cells, and their clinical relevance in various liver diseases.

Fig. 2 presents the compositions of the mononuclear cell populations of the liver and peripheral blood, as we demonstrated in a study using liver perfusate.⁴⁰ Importantly, the liver exhibits higher proportions of natural killer cells, mucosal-associated invariant T cells, and CD8⁺ T cells, whereas the peripheral blood shows a higher proportion of CD4⁺ T cells, suggesting that the liver constitutes a unique immune environment. CD69⁺CD8⁺ liver T_RM cells comprise 20% to 80% of liver CD8⁺ T cells.⁴⁰ Below we will summarize the unique characteristics of liver T_RM cells.

Figure 2. Comparison of the mononuclear cell populations in peripheral blood and liver sinusoidal perfusates. Pie charts indicate the proportions of different immune cell subsets in peripheral blood (A) and liver sinusoidal perfusate (B), as measured by flow cytometry. MAIT, mucosal-associated invariant T cells; NK, natural killer cells.

1. Location of liver T_RM cells

In most organs, T_RM cells reside within epithelial tissues or parenchyma; however, liver T_RM cells are mainly located within the sinusoids and constantly patrol the hepatic vasculature. The liver receives blood from both arterial and venous circulations, and the portal vein transports a significant volume of blood to the liver from the gastrointestinal tract and spleen. Upon reaching the liver, blood travels through narrow vascular capillaries called liver sinusoids, which slow the flow rate, enabling resident cells to interact with a wide range of antigens and circulating cells.⁴ The liver sinusoids are lined with a thin fenestrated layer of LSECs that separates hepatocytes from circulating cells. The fenestrae allow T cells in the blood to directly access the surface of hepatocytes or tissue stroma, facilitating antigen recognition and effector functions.^41,42 In summary, liver T_RM cells are located within the sinusoids and are continuously exposed to the bloodstream, which may affect their unique phenotypes and functions, compared to T_RM cells in other tissues that are anatomically isolated from the circulation.⁴³ Interestingly, intravital imaging has directly shown that liver T_RM cells have an amoeboid shape and are uniquely positioned in the vasculature, where they patrol the liver sinusoids at faster migration speeds compared to skin T_RM cells.^43-45

2. Formation of liver T_RM cells

During an immune response, local antigen presentation and inflammation significantly impact T_RM-cell differentiation and seeding within tissues.^43,46 However, the liver's vasculature ensures that circulating T_RM-cell precursors have direct access to liver T_RM-cell niches without having to leave the bloodstream. Therefore, T_RM cells are formed by local CD8⁺ T-cell proliferation, but can also be induced by adhesion molecules or chemokines. The retention of circulating T cells within liver sinusoids is initially facilitated by their docking to platelets, which adhere to sinusoidal hyaluronan in a CD44-dependent manner. Next, these T cells migrate along the liver sinusoids and recognize hepatocellular antigens, which can induce liver T_RM-cell differentiation.⁴¹ Another study reported that T cells may become trapped within liver sinusoids by LSECs, Kupffer cells, and hepatic stellate cells (HSCs), which promote increased expression of adhesion molecules, such as ICAM-1, VCAM-1, and VAP-1.⁴⁷ As T cells become trapped and migrate within the sinusoids, they interact with other cell types in the liver, which provide T_RM-inducing factors. Interactions with integrins, as well as chemokine receptors and their ligands, are crucial for liver T_RM cells. For example, CXCR6-CXCL16 interaction is essential for liver T_RM-cell retention, as is the interaction between LFA-1 and ICAM-1.^43,46,4

3. A unique functional characteristic of liver T_RM cells

The liver is well-known as an immune-tolerant organ, and this concept can also be applied to liver T-cell responses. Before the concept of T_RM cells emerged, investigations focused on liver T-cell characteristics, particularly their trapping, activation, and tolerance mechanisms. One early study provides a concise overview of liver T-cell responses, noting that activated T cells were trapped in the liver and subsequently underwent apoptosis, indicating that the liver not only accumulates T cells but can also promote their tolerance.⁴⁹

Under normal conditions, various gut-derived substances enter the liver through the portal vein, and the hepatic microenvironment influences liver T cells to become tolerant. To limit liver T-cell responses, HSCs express programmed death-ligand 1 (PD-L1), which triggers T-cell apoptosis.⁵⁰ Furthermore, antigen presentation by LSECs can induce antigen-specific T-cell tolerance via PD-1/PD-L1 interaction.⁵¹ Mouse HSCs can disrupt CD8⁺ T cells in an ICAM-1-dependent manner, thereby preventing their activation by antigen-presenting cells, and leading to apoptosis.⁴⁷ Hepatocytes can also prime CD8⁺ T cells, but they induce clonal T-cell deletion through a Bcl-2-interacting mediator of cell death-dependent pathway.⁵²

A recent study clearly demonstrated the role of LSECs in restricting liver T_RM-cell activation and function in a pre-clinical model of hepatitis B virus (HBV).⁵³ HBV-specific liver T_RM cells exhibited reduced function, which was induced by the adenylyl cyclase–cAMP–PKA axis and related to close contact with LSECs, suggesting that LSECs play a direct role in T-cell tolerance. Overall, these interactions between liver T cells and other cell populations contribute to the regulation of tolerance, which may differ among various clinical situations.

4. Comparisons between human and murine liver T_RM cells

Human and murine liver T_RM cells share several core characteristics. Firstly, they both exhibit upregulation of CD69, a representative marker of T_RM cells. This might reflect common mechanisms for retaining these cells within the liver sinusoids, and facilitating their interaction with antigens.^43,54 CXCR6 is also highly expressed in liver T_RM cells from both species. This chemokine receptor plays critical roles in the adhesion, accumulation, and maintenance of intrahepatic T cells. CXCL16, the ligand for CXCR6, is expressed by LSECs, Kupffer cells, and hepatocytes, which facilitates the residency of liver T_RM cells.^40,55,56 Moreover, in both humans and mice, liver T_RM cells are essential for mounting protective immune responses by producing cytokines (e.g., IFN-γ and TNF) and expressing cytotoxic molecules (e.g., granzyme B), although the expression levels may vary.^40,43 Additionally, both human and murine liver T_RM cells are critically influenced by IL-15, which is crucial for their development, maintenance, and homeostatic proliferation.^40,56,57

However, there are notable differences between human and murine liver T_RM cells, reflecting species-specific adaptations and functions. One striking difference is that murine liver T_RM cells do not express CD103, which is typically found in T_RM cells from other tissues, and is expressed by a subset of human liver T_RM cells (approximately 12.4%), indicating a species-specific divergence in the phenotypic characteristics of liver T_RM cells.^40,43,45,56 Among human liver T_RM cells, CD103⁺ cells produce more IFN-γ and IL-2 upon stimulation and express higher perforin levels, while CD103⁻ cells (although more numerous) show less cytokine production per cell and higher PD-1 expression.⁴⁰ The expression of hypoxia-inducible factor-2α in human CD103⁻ T_RM cells suggests unique regulatory mechanisms driven by the liver’s hypoxic environment, which has not been prominently reported in murine studies.^40,58 These differences highlight the importance of human-specific studies to fully understand human liver T_RM cells, and their implications for liver diseases and therapies.

Previous studies demonstrate that liver T_RM cells have special characteristics within the liver immune environment. In particular, their tolerant nature might play different roles in various liver diseases. Table 1 presents direct evidence regarding the liver T_RM population and its clinical relevance in human liver diseases. In the following sections, we will summarize the clinical and experimental studies of this topic, which reveal the dual roles of liver T_RM cells.

Table 1 . Human Studies of Liver T_RM Cells and their Clinical Correlations in Various Liver Diseases.

Author	Diseases	TRM phenotype	Clinical correlations from human subjects	Protective/pathologic
Pallett et al.56	HBV	CD69+CD103+CD8+	TRM↑ → HBV viral load ↓	Protective
Koda et al.66	MASLD	CD69+CD8+	TRM↑ → Fibrosis↓	Protective
Nkongolo et al.61	HBV	CXCR6+CD8+	Resolution of hepatitis → TRM↓	Pathologic
Kefalakes et al.63	HDV	CD69+CXCR6+CD8+	NKG2D↑ on TRM → Liver enzymes and APRI↑	Pathologic
Dudek et al.65	MASLD	CXCR6+CD8+	TRM↑ → ALT↑	Pathologic
You et al.67	AIH	CD69+CD103+CD8+	TRM↑ → ALT, histologic inflammation/fibrosis↑	Pathologic
Huang et al.70	PBC	CD103+CD8+	TRM↑ → ALP, GGT, TB↑, histologic inflammation/fibrosis↑	Pathologic
Kim et al.40	LC	CD69+CD103−CD8+	TRM activation↑ → MELD, Child-Pugh score↑	Pathologic

T_RM, tissue-resident memory T cells; HBV, hepatitis B virus; MASLD, metabolic-associated steatotic liver disease; HDV, hepatitis D virus; NKG2D, natural killer group 2D; APRI, aspartate transaminase (AST)-to-platelet ratio index; ALT, alanine aminotransferase; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; TB, total bilirubin; LC, liver cirrhosis; MELD, Model for End-Stage Liver Disease..

1. Viral hepatitis

T-cell responses are critical determinants of the clinical outcome of chronic HBV infection, and studies have also investigated liver T_RM cells’ roles and relationship with clinical outcomes. Murine models have provided clues indicating that liver T_RM cells are a potential target for treating chronic HBV infection. Interestingly, hepatic priming of intrahepatic CD8⁺ T cells induces dysfunctional responses, which can be restored by IL-2 treatment but not by anti-PD-L1 blockade.⁵⁹ Another study highlighted that the CXCL13-mediated accumulation of intrahepatic CXCR5⁺CD8⁺ T cells was correlated with decreased HBsAg levels, suggesting that liver T_RM cells may play a positive role in controlling HBV infection.⁶⁰

Studies have also characterized the protective role of human liver HBV-specific CD8⁺ T_RM cells in patients with chronic HBV infection.⁵⁶ Over 80% of liver HBV-specific CD8⁺ T cells express CD69, and the CD69⁺CD103⁺CD8⁺ subpopulation inversely correlates with HBV viral load, indicating a potential role in HBV control. This subpopulation also produces high IL-2 levels upon HBV-peptide stimulation, which may enhance HBV-specific T-cell responses. On the other hand, compared to CD103⁺ cells, our previous study demonstrated that CD69⁺CD103⁻CD8⁺ T_RM cells produce lower cytokine levels per cell upon HBV-peptide stimulation, although we did not investigate any direct correlations between clinical parameters.⁴⁰ Since the majority of human liver T_RM cells exhibit the CD103⁻ phenotype, understanding the hypofunction mechanisms and enhancing the function of CD69⁺CD103⁻CD8⁺ T_RM cells could be pivotal for HBV control.

The pathological roles of liver T_RM cells during HBV infection also warrant attention. A recent study identified highly activated liver CD8⁺ T_RM cells that were associated with liver damage in chronic hepatitis B patients.⁶¹ Upon in vitro stimulation with IL-2 and IL-12, these cells lysed target cells via FAS-FASL engagement, suggesting that bystander activation of T_RM cells during chronic HBV infection could be associated with eventual development of liver fibrosis and cirrhosis. This finding is reminiscent of the bystander activation of CD8⁺ T cells, which is associated with liver damage in acute hepatitis A virus infection.⁶² We demonstrated that IL-15 activated non-hepatotropic virus-specific liver T_RM cells,⁴⁰ suggesting that the bystander activation of liver T_RM cells contributes to liver damage in viral hepatitis. This phenomenon has also been observed in chronic hepatitis D virus infection.⁶³

2. Metabolic-associated steatotic liver disease

As observed in chronic HBV infection, liver T_RM cells also play dual roles in metabolic-associated steatotic liver disease (MASLD)—both promoting fibrotic processes and aiding in fibrosis resolution. Activated T_RM cells produce multiple cytokines, which are notably elevated in the liver and visceral fat of obese patients, potentially contributing to the inflammatory environment of the liver, and suggesting a possible association between liver damage and liver T_RM cells in MASLD patients.⁶⁴ This hypothesis has been elegantly proven by a recent study of human samples and mice.⁶⁵ It was demonstrated that MASLD patients exhibited elevated numbers of CD103⁺ or CXCR6⁺ T_RM cells, which displayed high surface levels of PD-1, but retained strong effector functions, with IL-15-induced production of IFN-γ, TNF, and granzyme B. These liver T_RM cells contributed to liver damage through non-specific cytotoxicity towards hepatocytes, especially upon downregulation of the transcription factor FOXO1. Overall, these findings indicate that the self-destructive behavior of CD8⁺ T cells is governed by mechanisms different from those involved in antigen-specific killing by CD8⁺ T cells.

On the other hand, a recent study found that CD69⁺CD103⁻CD8⁺ T_RM cells may play a protective role in resolving liver fibrosis in MASLD. CD69⁺CD103⁻CD8⁺ T_RM cells could contribute to fibrosis resolution by inducing apoptosis of HSCs. Accordingly, adoptive transfer of these cells protected mice from fibrosis progression in a CCR5-dependent manner.⁶⁶ Further studies are needed to explore the dual roles of T_RM cells in MASLD, and their specific mechanisms. Additionally, the role of liver T_RM cells in alcoholic liver disease remains to be elucidated.

3. Autoimmune liver disease

Liver T_RM cells also reportedly play a pathologic role in autoimmune liver diseases. In patients with autoimmune hepatitis, liver tissue exhibits high absolute numbers of CD8⁺ T_RM cells, which correlate with inflammation severity and fibrosis stage.⁶⁷ Additionally, IL-15 and TGF-β appear to support liver T_RM-cell maintenance and survival, as their intrahepatic expression is correlated with the number of these cells. In autoimmune hepatitis patients, glucocorticoid treatment reduces hepatic inflammation, and leads to decreased numbers of liver T_RM cells in tissue samples. Moreover, in vitro glucocorticoid treatment inhibits the expansion of T_RM cells induced by IL‐15 and TGF‐β, and leads to downregulated transcriptional activity of the BLIMP-1 gene.

Interestingly, a recent study of the biliary immune atlas revealed the presence of CD8⁺ T_RM cells in regions of biliary inflammation among patients with primary sclerosing cholangitis.⁶⁸ Another study demonstrated the expansion of liver CD4⁺ T_RM cells expressing genes associated with tissue residency, which are predisposed to polarize to Th17 cells.⁶⁹ In patients with primary biliary cholangitis, the frequency of CD8⁺ T_RM cells is positively correlated with cholestatic liver enzymes, histologic severity (in terms of inflammation and fibrosis), and responses to ursodeoxycholic acid.⁷⁰

4. Other liver diseases

In the context of liver cirrhosis, our investigations suggest that activation of CD69⁺CD103⁻ T_RM cells correlates with impaired liver function.⁴⁰ Similar to lung T_RM cells inducing chronic lung fibrosis after viral pneumonia,⁷¹ liver T_RM cells might be involved in the development of liver fibrosis or cirrhosis in chronic HBV infection.

In organ transplant recipients, small numbers of donor cells can reportedly persist in allografts for over a decade, including CXCR3^hi CD8⁺ T_RM cells in liver transplants.⁷² These cells were also present in local lymph nodes, but did not egress into the hepatic vein. The presence of long-lived T_RM-cell populations in liver allografts may have implications regarding liver transplantation; however, their role in rejection or other pathologic states remains to be elucidated.

5. Liver stage of malaria

Liver CD8⁺ T_RM cells are pivotal in the immune defense against the liver stage of malaria. Murine studies of liver-stage malaria have provided mechanistic insights regarding the generation and maintenance of liver CD8⁺ T_RM cells, which provide immediate protection by patrolling the liver sinusoids and quickly responding to sporozoite infections. Immunization with radiation-attenuated sporozoites activates liver CD8⁺ T_RM cells, which are crucial for sterile immunity against malaria.⁴³ Moreover, depletion of these cells results in loss of protective immunity, emphasizing their importance.⁴³ Studies of non-human primates show that intravenous immunization with attenuated sporozoites induces parasite-specific CD8⁺ T_RM cells in the liver, conferring protection similar to that observed in murine models.⁷³ These findings suggest that the mechanisms identified in animal studies can guide the development of effective malaria vaccines. Future research should focus on optimizing vaccination strategies to enhance CD8⁺ T_RM-cell generation and function in humans, which may lead to development of highly effective malaria vaccines.

6. Study of liver T_RM cells using clinical specimens

Immune cells are isolated from liver tissue samples—such as percutaneous core-needle biopsy or surgical specimens—using a combination of enzymatic and mechanical dissociation.^74,75 Briefly, fresh liver tissues are treated with enzymes, e.g., collagenase and DNase, to break down the extracellular matrix. The resulting suspension is gently homogenized, and then separated by density gradient centrifugation. After centrifugation, the immune cell layer is carefully collected, washed, and resuspended in culture medium. This immune cell population includes liver T_RM cells, and can be used for analyses of liver T_RM cells, as previously described.^40,56

Fine-needle aspiration (FNA) offers several advantages over traditional needle biopsy, including that FNA is less invasive, better tolerated, and allows for repeated longitudinal sampling. During the procedure, a thin 22-gauge spinal needle is inserted into the liver parenchyma, and cells are aspirated with gentle negative pressure. FNA sample preparation typically involves collecting the aspirate in a culture medium, and centrifuging it to obtain a cell pellet, followed by treatment with red blood cell lysis buffer before analysis.⁷⁶ Importantly, it has been demonstrated that FNA reliably samples liver T_RM cells, although at slightly lower frequencies compared to in core-needle biopsy samples.⁷⁶

Liver perfusate collection offers an alternative method for isolating intrahepatic immune cells, including liver T_RM cells.^77-79 During liver transplantation, graft livers are perfused with a preservation solution. The perfusate is collected, filtered, and centrifuged to isolate immune cells. Finally, liver sinusoidal mononuclear cells are separated using density gradient centrifugation. The main limitation of this technique is its dependence on liver transplantation procedures. Notably, it provides the significant advantage of yielding a large number of cells, which enables extensive and comprehensive analyses.

In this comprehensive review, we highlight the crucial roles and unique characteristics of T_RM cells in the liver, which exhibit distinct profiles that enable their tissue residency and functionality. Liver T_RM cells are uniquely situated within the liver sinusoids, enabling continuous interaction with circulating antigens for immune surveillance. In particular, we have summarized the protective and pathological roles of liver T_RM cells in various human liver diseases—including viral hepatitis, steatotic liver disease, and autoimmune liver disease.

Future research should focus on elucidating the detailed mechanisms governing the formation, maintenance, and function of T_RM cells in the liver. This work will improve our understanding of the balance between these cells’ protective roles and potential contributions to pathology. Such insights could inform the development of targeted therapies aimed at enhancing the beneficial functions of T_RM cells, while mitigating their detrimental effects. Moreover, the potential use of liver T_RM cells in vaccine development, particularly for diseases like malaria, presents an exciting avenue for translational research.

In conclusion, liver T_RM cells constitute a critical component of hepatic immunity, and have significant implications regarding a wide range of liver diseases. Advancing our understanding of these cells will enhance our knowledge of liver immunology, as well as pave the way for novel therapeutic strategies in liver disease management.

This study was supported by the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea (J.W.H.), by the Institute for Basic Science (IBS), Republic of Korea, under project code IBS-R801-D2 (E.C.S.) and by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2024-00439160; E.C.S.).

No potential conflict of interest relevant to this article was reported.

J.W.H. and E.C.S. wrote, reviewed, and submitted the manuscript.