Mucosal-associated invariant T cells in hepatitis B virus-related liver failure

BACKGROUND Liver failure has high mortality and poor prognosis,and establishing new reliable markers for predicting its prognosis is necessary.Mucosal-associated invariant T(MAIT)cells are a novel population of innate-like lymphocytes involved in inflammatory liver disease,and their potential role in liver failure remains unclear.AIM To investigate alteration of circulating MAIT cells and assess its prognostic value in patients with hepatitis B virus(HBV)-related liver failure.METHODS We recruited 55 patients with HBV-related liver failure,48 patients with chronic hepatitis B and 40 healthy controls(HCs)from Nantong Third People’s Hospital Affiliated to Nantong University.Peripheral blood mononuclear cells were isolated,and the percentage and number of circulating MAIT cells were detected by flow cytometry.Plasma levels of interleukin(IL)-7,IL-12p70,IL-18 and interferon-αwere measured by Luminex assay.RESULTS Circulating MAIT cells were significantly decreased in HBV-related liver failure patients(percentage:2.00±1.22 vs 5.19±1.27%,P<0.0001;number:5.47±4.93 vs 84.43±19.59,P<0.0001)compared with HCs.More importantly,there was a significant reduction of MAIT cells in patients with middle/late-stage compared with early-stage liver failure.Circulating MAIT cells partially recovered after disease improvement,both in percentage(4.01±1.21 vs 2.04±0.95%,P<0.0001)and in cell count(17.24±8.56 vs 7.41±4.99,P<0.0001).The proportion(2.29±1.01 vs 1.58±1.38%,P<0.05)and number(7.30±5.70 vs 2.94±1.47,P<0.001)of circulating MAIT cells were significantly higher in the survival group than in the dead/liver transplantation group,and the Kaplan–Meier curve showed that lower expression of circulating MAIT cells(both percentage and cell count)predicted poor overall survival(P<0.01).Also,the levels of IL-12(20.26±5.42 pg/mL vs 17.76±2.79 pg/mL,P=0.01)and IL-18(1470.05±1525.38 pg/mL vs 362.99±109.64 pg/mL,P<0.0001)were dramatically increased in HBV-related liver failure patients compared with HCs.CONCLUSION Circulating MAIT cells may play an important role in the process of HBV-related liver failure and can be an important prognostic marker.

Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

Mucosal-associated invariant T(MAIT)cells have been described in liver and nonliver diseases,and they have been ascribed antimicrobial,immune regulatory,protective,and pathogenic roles.The goals of this review are to describe their biological properties,indicate their involvement in chronic liver disease,and encourage investigations that clarify their actions and therapeutic implications.English abstracts were identified in PubMed by multiple search terms,and bibliographies were developed.MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines.Diverse pro-inflammatory,anti-inflammatory,and immune regulatory cytokines are released;infected cells are eliminated;and memory cells emerge.Circulating MAIT cells are hyper-activated,immune exhausted,dysfunctional,and depleted in chronic liver disease.This phenotype lacks disease-specificity,and it does not predict the biological effects.MAIT cells have presumed protective actions in chronic viral hepatitis,alcoholic hepatitis,non-alcoholic fatty liver disease,primary sclerosing cholangitis,and decompensated cirrhosis.They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis.Local factors in the hepatic microenvironment(cytokines,bile acids,gut-derived bacterial antigens,and metabolic by-products)may modulate their response in individual diseases.Investigational manipulations of function are warranted to establish an association with disease severity and outcome.In conclusion,MAIT cells constitute a disease-nonspecific,immune response to chronic liver inflammation and infection.Their pathological role has been deduced from their deficiencies during active liver disease,and future investigations must clarify this role,link it to outcome,and explore therapeutic interventions.

Mucosal-associated invariant T cells from induced pluripotent stem cells:A novel approach for modeling human diseases

Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the development of novel therapies.However,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good example.MAIT cells are abundant in humans but scarce in laboratory mice.MAIT cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and yeasts.Recent studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory diseases.MAIT cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in mice.Furthermore,MAIT cells show poor proliferation in vitro.To overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.

Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients

Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.

Human CD4- CD8- Invariant Natural Killer T Cells Promote IgG Secretion from B Cells Stimulated by Cross-Linking of Their Antigen Receptors

Immunoglobulin (Ig) M production can be induced by the interaction of thymus-independent type-2 (TI-2) antigen (Ag) with B cell Ag receptors (BCRs) without the involvement of conventional T cells;for IgG production through the same process, however, a second signal is required. Previous studies have reported that invariant natural killer T (iNKT) cells may be responsible for the second signal involved in IgG production. In the present study, we addressed whether human iNKT cells could participate in the production of Ig against TI-2 Ag in vitro. Two major distinct subsets of human iNKT cells, CD4+ CD8β- (CD4) and CD4- CD8β- [double negative (DN)] cells, were generated from peripheral blood monocytes from a healthy volunteer. BCR engagement, triggered by anti-IgM antibody stimulation, examined here as a model of BCR engagement triggered by TI-2 Ag, induced abundant IgM production by B cells. Both CD4 and DN iNKT cells reduced IgM production and conversely enhanced IgG production in a dose-dependent manner. In addition, IgG production by CD19+CD27- (naïve) and CD19+CD27+ (memory) B cells was predominantly promoted by DNiNKT cells rather than CD4 iNKT cells;nevertheless, IgM production by both B cell subsets was similarly reduced by either subset of iNKT cells. These results suggest that the DN iNKT subsets may preferentially promote Ig class switching by B cells upon stimulation with TI-2 Ag.

SRSF1 plays a critical role in invariant natural killer T cell development and function

Invariant natural killer T(iNKT)cells are highly conserved innate-like T lymphocytes that originate from CD4^(+)CD8^(+)double-positive(DP)thymocytes.Here,we report that serine/arginine splicing factor 1(SRSF1)intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms.Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation,survival,and TCRαrearrangement.The transition from stage 0 to stage 1 of iNKT cells was substantially blocked,and the iNKT2 subset was notably diminished in SRSF1-deficient mice.SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation,including Myb,PLZF,Gata3,ICOS,and CD5.In particular,we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells.Strikingly,ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1.Furthermore,we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury uponα-GalCer and Con A induction.Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation,providing new clinical insights into iNKT-correlated disease.

MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function

MicroRNAs(miRNAs)are an abundant class of evolutionarily conserved,small,non-coding RNAs that post-transcriptionally regulate expression of their target genes.Emerging evidence indicates that miRNAs are important regulators that control the development,differentiation and function of different immune cells.Both CD4^(+)CD25^(+)Foxp3^(+) regulatory T(Treg)cells and invariant natural killer T(iNKT)cells are critical for immune homeostasis and play a pivotal role in the maintenance of self-tolerance and immunity.Here,we review the important roles of miRNAs in the development and function of iNKT and Treg cells.