Adaptive Immunity Research Articles

Bioinformatic characterization of STING expression in hematological malignancies reveals association with prognosis and anti-tumor immunity

IntroductionStimulator of interferon response cGAMP interactor (STING) is essential for both innate and adaptive immunity. However, a comprehensive molecular characterization of STING expression across hematological malignancies is lacking.MethodsIn this study, the pan-blood-cancer landscape related to STING expression was identified using the GTEx, CCLE, Hemap, and TCGA databases, and the potential value for predicting prognosis was investigated. The relationship between STING expression and immune cell enrichment was assessed in the Hemap database. Moreover, the value of STING in predicting the efficacy of immunotherapy was validated using tumor immune dysfunction and exclusion (TIDE) biomarkers and real-world immunotherapy datasets.Results and DiscussionSTING was found to be relatively highly expressed in acute myeloid leukemia (AML) and chronic myeloid leukemia, with higher STING expression correlated with poorer prognosis in AML. STING expression was positively correlated with immune-related pathways such as IFN-gamma response, IFN-alpha response, and inflammatory response. Cytolytic score and STING expression were positively correlated in some hematological tumors, especially chronic lymphocytic leukemia and mantle cell lymphoma. Interestingly, STING expression was negatively correlated with TIDE biomarkers in AML, suggesting that AML patients with a high STING expression level may benefit from immunologic treatment. Our findings contribute a molecular characterization of STING across hematological malignancies, facilitating the development of individualized prognosis and treatment strategies.

Qualitative Analysis of a Fractional-Order for a Within-Host Infection Dynamics with Adaptive Immunity Using Caputo Derivative

Qualitative Analysis of a Fractional-Order for a Within-Host Infection Dynamics with Adaptive Immunity Using Caputo Derivative

Generation and characterization of chicken monocyte-derived dendritic cells

IntroductionDendritic cells (DCs) play a crucial role in orchestrating immune responses by bridging innate and adaptive immunity. In vitro generation of DCs from mouse and human tissues such as bone marrow and peripheral blood monocytes, has been widely used to study their immunological functions. In chicken, DCs have mainly been derived from bone marrow cell cultures, with limited characterization from blood monocytes.MethodsThe present study takes advantage of newly available chicken immunological tools to further characterize chicken monocyte-derived dendritic cells (MoDCs), focusing on their phenotype, and functions, including antigen capture and T-cell stimulation, and response to live Newcastle disease virus (NDV) stimulation.ResultsAdherent chicken PBMCs were cultured with recombinant chicken granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), for 5 days, leading to the upregulation of putative CD11c and MHCII, markers of DC differentiation. Subsequent stimulation with lipopolysaccharide (LPS) or 24 h triggered phenotypic maturation of MoDCs, characterized by the increased surface expression of MHCII and co-stimulatory molecules CD80 and CD40, and elevated IL-12p40 secretion. This maturation reduced endocytic capacity but enhanced the allogenic stimulatory activity of the chicken MoDCs. Upon NDV stimulation for 6 h, MoDCs upregulated antiviral pathways, including retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), alongside increased production of type I interferons (IFNs), and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β, and IL-6. However, these responses were downregulated after 24 hours.ConclusionThese findings provide a comprehensive characterization of chicken MoDCs and suggest their potential as a model for studying host-pathogen interactions.

Idiopathic Subglottic Stenosis and the Epithelial Interface of Host and Environment.

Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis. Harnessing pathogenic mucosa from an international iSGS patient cohort and single cell RNA sequencing we provide an unbiased characterization of the cell subsets present in the proximal airway scar and detail their molecular phenotypes. Airway epithelium in iSGS patients is depleted of basal progenitor cells and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disrupted bacterial community structure. However, animal models confirm bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis. Our novel data support an iSGS disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Overall, these results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.

Imaging Antigen Processing and Presentation in Cancer

Abstract Introduction Antigen processing and presentation are vital processes of the adaptive immunity. These processes involve a series of intracellular and extracellular events, including the enzymology within cells during antigen processing, the loading and presentation of antigenic peptides on major histocompatibility complexes, the recruitment of T cells, their interaction with antigen-presenting cells, and the expression of adhesion, co-stimulatory and co-inhibitory molecules at the T cell immunological synapse. These events collectively fine-tune and sustain antigen recognition and T cell function. Dysregulation of this machinery can profoundly impact the efficacy of cancer immunotherapy. Imaging technologies have emerged as powerful tools for elucidating the mechanisms underlying antigen processing and presentation. By providing complementary perspectives into the cellular and molecular interactions at play, imaging has significantly enhanced our understanding of these complex immunological events in cancer. Such insights can improve the monitoring of immunotherapy responses, facilitate the identification of effective treatments, and aid in predicting patient outcomes. Methods This review explores the role of imaging in studying antigen processing and presentation in the context of cancer. Conclusion It highlights key considerations for developing imaging tools and biomarkers to detect components of these pathways. Additionally, it examines the strengths and limitations of various imaging approaches and discusses their potential for clinical translation.

Comment on the article “The role of innate and adaptive immunity in Wallerian degeneration in peripheral nerve crush injury”

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Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence.

The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.

The Role of Mucosal-Associated Invariant T Cells in Viral Infections and Their Function in Vaccine Development

Mucosal-Associated Invariant T (MAIT) cells, which bridge innate and adaptive immunity, have emerged as an important player in viral infections despite their inability to directly recognize viral antigens. This review provides a comprehensive analysis of MAIT cell responses across different viral infections, revealing consistent patterns in their behavior and function. We discuss the dynamics of MAIT cells during various viral infections, including changes in their frequency, activation status, and functional characteristics. Particular attention is given to emerging strategies for MAIT-cell-targeted vaccine development, including the use of MR1 ligands as mucosal adjuvants and the activation of MAIT cells through viral vectors and mRNA vaccines. Current knowledge of MAIT cell biology in viral infections provides promising approaches for harnessing their functions in vaccine development.

Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon.

Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium-induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.

Immunological Effects of Electronic Cigarette Use: A Review of Current Evidence.

Electronic cigarettes (EC) have emerged as a popular alternative to traditional tobacco products, but their impact on immune function has raised significant health concerns. This review explores the immunological effects of EC exposure, focusing on innate and adaptive immune responses. Electronic cigarette aerosol (ECA) induces widespread inflammation. These changes compromise immune cell function, impairing neutrophil chemotaxis, phagocytosis, and oxidative burst while increasing macrophage and dendritic cell recruitment and activation. ECA also disrupts epithelial barriers, increasing susceptibility to bacterial and viral infections. Studies show enhanced biofilm formation in bacteria such as Staphylococcus aureus and Streptococcus pneumoniae and impaired antiviral responses against pathogens like influenza A and SARS-CoV-2. Additionally, EC exposure modulates adaptive immunity, affecting T and B cell function and increasing systemic inflammatory markers. The long-term consequences of these immunological disruptions include heightened risks for chronic inflammatory diseases, respiratory infections, and potentially autoimmune conditions. The widespread adoption of EC, particularly among younger users, poses a growing public health challenge. As the popularity of vaping continues to rise, these immunological disruptions could result in increased healthcare burdens in the future, with higher rates of infections, chronic inflammatory diseases, and immune system-related disorders among those who begin using e-cigarettes at a young age. Understanding the full scope of EC-related health risks is essential for informing public health policies and protecting future generations from the potential long-term effects of vaping.

Identification of RP-54745, an IL-1 Inhibitor Displaying Anticancer Activities for KSHV-Related Primary Effusion Lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin-1 (IL-1) family is a major mediator for inflammatory responses and has functional role in both innate and adaptive immunity. We previously showed high activation of multiple IL-1 signaling molecules during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. In the current study, we identified RP-54745, a potential antirheumatic compound as IL-1 inhibitor, effectively repressed KSHV + PEL cell growth through inducing tumor cell apoptosis. By using an established PEL xenograft model, we found that RP-54745 treatment suppressed tumor expansion in mice. Also, RP-54745 treatment significantly reduced hyperinflammation in tumor microenvironment including myeloid cells and neutrophils infiltration, as well as blocking IL-1 signaling molecules expression in vivo. In addition, our transcriptome analysis revealed novel cellular genes and mechanisms for anticancer activities of RP-54745. Taken together, our data indicate targeting IL-1 production and signaling may represent promising therapeutic strategies against these virus-associated diseases.

ATM in immunobiology: From lymphocyte development to cancer immunotherapy.

Ataxia Telangiectasia Mutated (ATM) is a protein kinase traditionally known for its role in DNA damage response and cell cycle regulation. However, emerging research has revealed its multifaceted and crucial functions in the immune system. This comprehensive review explores the diverse roles of ATM in immune regulation, from lymphocyte development to its involvement in cancer immunotherapy. The review describes ATM's critical functions in V(D)J recombination and class switch recombination, highlighting its importance in adaptive immunity. It examines ATM's role in innate immunity, particularly in NF-κB signaling and cytokine production. Furthermore, the review analyzes the impact of ATM deficiency on oxidative stress and mitochondrial function in immune cells, providing insights into the immunological defects observed in Ataxia Telangiectasia (A-T). The article explores ATM's significance in maintaining hematopoietic stem cell function and its implications for bone marrow transplantation and gene therapy. Additionally, it addresses ATM's involvement in inflammation and immune senescence, linking DNA damage response to age-related immune decline. Finally, this review highlights the emerging role of ATM in cancer immunotherapy, where its inhibition shows promise in enhancing immune checkpoint blockade therapy. This review synthesizes current knowledge on ATM's functions in the immune system, offering insights into the pathophysiology of ATM-related disorders and potential therapeutic strategies for immune-related conditions and cancer immunotherapy.

Control of Mycobacterium tuberculosis infection in the elderly: Is there a role for epigenetic reprogramming reversal?

With the increase in the elderly population worldwide, the number of subjects suffering from tuberculosis (TB) has shown an increased prevalence in this group. Immunosenescence is essential in this phenomenon because it may reactivate the lesions and render their adaptive immunity dysfunctional. In addition, inflammation in the lungs of the elderly subjects is also dysfunctional. Although effective drugs are available, they are often tolerated inadequately, reducing adherence to the therapy and leading to therapeutic failure. Comorbidities, poor general health status, and other medications may lead to increased drug adverse reactions and reduced adherence to treatment in the elderly. Hence, older adults require an individualized approach for better outcomes. Trained immunity, which involves epigenetic reprogramming, may contribute to balancing the dysfunction of innate and adaptive immunity in older people. This review analyzes the relationship between inflammation, age, and Mycobacterium tuberculosis. Moreover, we hypothesize that immunomodulation using trained immunity activators will help reduce inflammation while enhancing antimicrobial responses in the elderly. Understanding immunomodulation's molecular and physiological effects will lead to informed decisions about TB prevention and treatment strategies uniquely designed for the elderly.

Abstract 14: A distinct clot transcriptomic signature is associated with atrial fibrillation-derived ischemic stroke in the INSIGHT Registry

Funding: The INSIGHT Registry is funded by Penumbra. Introduction: Rapid and precise determination of the etiology of acute ischemic stroke is crucial in long-term management and prevention of recurrence. Identification of etiology-associated molecular biomarkers following thrombectomy may allow for personalized intervention. Here, we examine the transcriptomics of cardioembolic thrombi as a result of atrial fibrillation, identifying a distinct transcriptomic signature relative to other causes of ischemic stroke. Methods: The INSIGHT registry is a prospective, multicenter, multi-omic registry focused on elucidating the molecular underpinnings of stroke from analysis of clot and interarterial blood. RNA sequencing of 10,990 genes from 292 thrombi from patients undergoing thrombectomy was analyzed using edgeR, sva, and limma/voom. 111 patients had a determined etiology of atrial fibrillation. Controls had unknown, atheroembolic, or coagulopathy stroke etiology. Significant association of thrombus gene expression with atrial fibrillation was conducted using the Wilcoxon Rank Sum test using Benjamini-Hochberg multiple testing correction (FDR <5%). Gene set enrichment was performed using FGSEA using Gene Ontology biological processes gene sets. Co-expression modules were detected using WGCNA and analyzed using cytoscape. Results: 33 genes (27 upregulated, 6 downregulated) within thrombi were significantly associated with atrial fibrillation etiology. These included upregulated endothelial cell markers associated with cardiac endothelial cells (e.g. KDR , AMDHD2 , IL18BP ) compared to thrombi of other etiologies. In addition, upregulated genes were associated with oxidative stress (FDR= 8.46x10 -8 ) and metabolism (1.04x10 -6 ), while adaptive T-cell immunity was downregulated (FDR= 7.52x10 -3 ). Co-expressed gene networks upregulated by atrial fibrillation-associated thrombi included a module implicated in innate immune signaling and cytotoxic granule release (p=0.02), which included key hub genes GZMH and TBX21. Conclusion: Cardioembolic thrombi possess a distinct transcriptomic signature consistent with collection and retainment of cardiac endothelial tissue at origin, and display immunomodulatory activity associated with innate vs adaptive immune balance. This signature suggests the active role thrombi likely play in the vascular microenvironment and may ultimately be used to identify atrial fibrillation as an etiology in strokes of unknown origin.

Promoting macrophage phagocytosis of cancer cells for effective cancer immunotherapy.

Cancer therapy has been revolutionized by immunotherapeutic agents exploiting adaptive antitumor immunity in the past two decades. However, the overall response rate of these immunotherapies is limited, and patients also develop resistance upon treatment, promoting a rapidly growing exploration of anti-tumor innate immunity for effective cancer therapy. Among these, macrophage immunotherapy through harnessing macrophage phagocytosis has been thrust into the spotlight due to its potential for simultaneously inducing cancer cell killing effect and mobilizing adaptive antitumor responses. Here in this review, we summarize the current macrophage immunotherapy such as therapeutic antibodies, phagocytosis checkpoint blockades, and CAR-macrophages with a particular emphasis on the resistant mechanisms limiting their therapeutic effects. Moreover, we further survey the efforts being placed to seek synergistic mechanisms and combination strategies for promoting macrophage phagocytosis which might stand as next-generation cancer immunotherapy.

Transcriptome analyses of mRNA and circular RNA reveal dietary supplementation with freeze-dried Lactiplantibacillus plantarum primes immune memory of Whiteleg shrimp (Penaeus vannamei) against pathogens.

The lack of a classical adaptive immunity renders the development of disease control and prevention measures in shrimp challenging. In this study, the concept of trained immunity was exploited in the development of a feed supplement. Penaeus vannamei shrimp was fed with feed supplemented with freeze-dried whole culture of Lactiplantibacillus plantarum (FD-LAB) for 15 days. RNA sequencing using Illumina platform was performed on the gill and stomach tissues collected at specific time points during the feeding period (0th day, 8th day, 15th day). Differentially-expressed genes (DEGs) previously reported to have innate immunity- and immune memory-related functions were selected for validation. Additionally, the differential expression of putatively immune-related circular RNAs (DECs) were also explored as these noncoding regulatory RNAs may also influence host immunity. Challenge tests with either the acute hepatopancreatic necrosis disease-causing strain Vibrio parahaemolyticus D6 or White Spot Syndrome Virus (WSSV) were conducted. Transcriptome analyses showed that FD-LAB supplementation resulted to DEGs and DECs related to pathogen recognition, antimicrobial peptides, transcription regulation, and immune memory. Challenge tests performed immediately after 15 days and 8 days of feeding showed protection on P. vannamei by FD-LAB against bacterial and viral pathogens. Increase in survival rates were also observed upon challenge with both pathogens 7 days and 14 days after last intake of FD-LAB, indicating trained immunity in shrimp. Our study highlighted the effects of FD-LAB on the innate immunity and immune memory of P. vannamei against bacterial and viral pathogens. These findings emphasize the possibility of immunostimulants inducing lasting enhanced immunity against infections despite the lack of a classical adaptive immunity in shrimp.

Dysfunction in neuro-mesenchymal units impairs the development of bone marrow B cells in mice with anxiety.

The reduction in B lymphocytes observed in individuals with anxiety disorders may compromise antiviral responses, yet the precise mechanisms behind this decline remain unclear. While elevated glucocorticoid levels have been suggested as contributing factors, anxiety disorders are associated with diminished glucocorticoid signaling. Given that autonomic nervous system dysfunction is a hallmark of anxiety disorders, we established an anxiety-related behavior mouse model by stimulating C1 neurons in the rostral ventrolateral medulla. Using this model, we confirmed that sustained activation of sympathetic nerves can disrupt adaptive immunity, particularly affecting the development of B cells. The underlying mechanism involves the control of B cell development through neuro-mesenchymal units within the bone marrow, with mesenchyme-derived CXCL12 playing a pivotal role in this regulatory process. Intriguingly, targeting these neuro-mesenchymal units not only restored B cell development but also alleviated anxiety-like behavior in the mice. Our study provides compelling evidence regarding the regulatory role of neuro-mesenchymal units in the development of B cells within the bone marrow. Additionally, our findings suggest that anxiety disorders can create a vicious cycle, perpetuating ongoing mental and immunological damage and ultimately leading to irreversible harm. To break this cycle, it is essential to focus on the dysfunction of immune cells and strive to restore immune homeostasis in individuals suffering from anxiety disorders.

Berberine shaping the tumor immune landscape via pyroptosis.

Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.

Crystal structure of the anti-CRISPR protein AcrIE7.

Bacterial adaptive immunity, driven by CRISPR-Cas systems, protects against foreign nucleic acids from mobile genetic elements (MGEs), like bacteriophages. The type I-E CRISPR-Cas system employs the Cascade (CRISPR-associated complex for antiviral defense) complex for target DNA cleavage, guided by crRNA. Anti-CRISPR (Acr) proteins, such as AcrIE7, counteract this defense by inhibiting Cascade activity. In this study, we characterized and determined the structure of AcrIE7, a unique member of the AcrIE family, using X-ray crystallography under two distinct crystallization conditions, achieving resolutions of 2.05Å and 2.68Å, respectively. Topological analysis revealed that AcrIE7 consists of seven α-helices with two distinct charge regions, likely mediating its inhibitory interactions. Structural flexibility analysis revealed notable structural stability differences between the two crystallization conditions, indicating varying rigidity of the AcrIE7 protein under different conditions. Homology searches and AlphaFold predictions reinforced the unique nature of AcrIE7, which exhibits a novel fold, underscoring its distinct role within the AcrIE family. These findings enhance our understanding of Acr proteins and provide a theoretical foundation for developing CRISPR-based gene-editing regulatory tools.

EXPRESS: Unlocking the Immune Puzzle: T Cell exhaustion in cirrhosis and implication for immunotherapy.

Cirrhosis, an advanced stage of liver diseases, induces Cirrhosis-Associated Immune Dysfunction Syndrome (CAIDS) characterized by both innate and adaptive immune dysfunction. Inflammation triggered by factors such as alcohol, viruses, toxins, and cholesterol induce metabolic reprogramming of both innate and adaptive immune cells. Our study specifically sought to investigate the compromised adaptive immune response in cirrhosis by focusing on assessing T-cell exhaustion and activation markers on helper and cytotoxic T cells. A prospective observational study involving 19 liver cirrhosis patients and 36 healthy controls was conducted. Hepatic decompensation degree was assessed using various parameters including serum bilirubin, albumin, international normalized ratio, ascites and hepatic encephalopathy. T cell activation (CD38, CD44, CD69, HLADR), and exhaustion markers (CTLA-4, PD-1, TIM-3, LAG-3) were assessed on helper and cytotoxic T cells by flow cytometry. Cirrhosis patients showed reduced T cells with no alteration in CD4:CD8 T cell ratio. Among activation markers, HLADR showed increased expression on CD8+ T cells (P=0.031). Regarding exhaustion markers LAG-3 and TIM-3 exhibited increased expression in cirrhotic patients compared to controls in both CD4 and CD8 T cells (P=0.004, P=0.016, P=0.001, P=0.004, respectively). Neither cirrhotic nor healthy controls showed CTLA expression. PD-1 did not differ significantly between the two groups. Co-expression of PD-1/TIM-3 on CD8+ T cells was notably higher in cirrhotic patients (P<0.002). The observation of impaired adaptive immunity with notable T cell exhaustion and activation in cirrhosis underscores the potential relevance of immunotherapy.