scholarly journals Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting

2021 ◽  
Vol 12 ◽  
Author(s):  
Avuyonke Balfour ◽  
Charlotte Schutz ◽  
Rene Goliath ◽  
Katalin A. Wilkinson ◽  
Sumaya Sayed ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Functional Impairment ◽  
Functional Profile ◽  
Functional Changes ◽  
Mait Cells ◽  
Endemic Setting ◽  
Tb Treatment ◽  
Hla Dr ◽  
Mait Cell

Background: MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ.Methods: We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, n = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, n = 36), (iii) individuals with HIV infection (HIV, n = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, n = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) Mycobacterium tuberculosis (M.tb) were analyzed using flow cytometry. MAIT cells were defined as CD3+ CD161+ Vα7.2+ T cells.Results: Circulating MAIT cell frequencies were depleted in individuals with HIV infection (p = 0.009). MAIT cells showed reduced CD107a expression in aTB (p = 0.006), and reduced IFNγ expression in aTB (p < 0.001) and in HIV-TB (p < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV (p < 0.001), aTB (p = 0.019), and HIV-TB (p = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB (p = 0.009) and HIV-TB (p = 0.002) after stimulation with BCG-GFP and HK-M.tb. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a (p = 0.020) and IFNγ (p = 0.010) expression.Conclusions: Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.

scholarly journals Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1

2020 ◽  
Vol 5 (49) ◽  
pp. eabc9492 ◽  
Author(s):  
Lauren J. Howson ◽  
Wael Awad ◽  
Anouk von Borstel ◽  
Hui Jing Lim ◽  
Hamish E. G. McWilliam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Bacterial Infections ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Mait Cells ◽  
History Of ◽  
Antigen Presenting ◽  
Mait Cell

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.

scholarly journals Polyclonal Mucosa-Associated Invariant T Cells Have Unique Innate Functions in Bacterial Infection

2012 ◽  
Vol 80 (9) ◽  
pp. 3256-3267 ◽  
Author(s):  
Wei-Jen Chua ◽  
Steven M. Truscott ◽  
Christopher S. Eickhoff ◽  
Azra Blazevic ◽  
Daniel F. Hoft ◽  
...  
Keyword(s):  
T Cells ◽  
Bacterial Infection ◽  
Cell Function ◽  
Interleukin 12 ◽  
Minor Role ◽  
Microbial Infection ◽  
Bacterial Strains ◽  
Unique Role ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosa-associated invariant T (MAIT) cells are a unique population of αβ T cells in mammals that reside preferentially in mucosal tissues and express an invariant Vα paired with limited Vβ T-cell receptor (TCR) chains. Furthermore, MAIT cell development is dependent upon the expression of the evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule MR1. Usingin vitroassays, recent studies have shown that mouse and human MAIT cells are activated by antigen-presenting cells (APCs) infected with diverse microbes, including numerous bacterial strains and yeasts, but not viral pathogens. However, whether MAIT cells play an important, and perhaps unique, role in controlling microbial infection has remained unclear. To probe MAIT cell function, we show here that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth ofMycobacterium bovisBCG in macrophages (MΦ) in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ. Surprisingly, however, the cognate recognition of MR1 by MAIT cells on the infected MΦ was found to play only a minor role in MAIT cell effector function. We also report that MAIT cell-deficient mice had higher bacterial loads at early times after infection compared to wild-type (WT) mice, demonstrating that MAIT cells play a unique role among innate lymphocytes in protective immunity against bacterial infection.

scholarly journals MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection

2016 ◽  
Vol 213 (12) ◽  
pp. 2793-2809 ◽  
Author(s):  
Anda I. Meierovics ◽  
Siobhán C. Cowley
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Monocyte Differentiation ◽  
Gm Csf ◽  
Mait Cells ◽  
Inflammatory Monocytes ◽  
Deficient Mice ◽  
Mait Cell ◽  
Csf Production

Mucosa-associated invariant T (MAIT) cells are a unique innate T cell subset that is necessary for rapid recruitment of activated CD4+ T cells to the lungs after pulmonary F. tularensis LVS infection. Here, we investigated the mechanisms behind this effect. We provide evidence to show that MAIT cells promote early differentiation of CCR2-dependent monocytes into monocyte-derived DCs (Mo-DCs) in the lungs after F. tularensis LVS pulmonary infection. Adoptive transfer of Mo-DCs to MAIT cell–deficient mice (MR1−/− mice) rescued their defect in the recruitment of activated CD4+ T cells to the lungs. We further demonstrate that MAIT cell–dependent GM-CSF production stimulated monocyte differentiation in vitro, and that in vivo production of GM-CSF was delayed in the lungs of MR1−/− mice. Finally, GM-CSF–deficient mice exhibited a defect in monocyte differentiation into Mo-DCs that was phenotypically similar to MR1−/− mice. Overall, our data demonstrate that MAIT cells promote early pulmonary GM-CSF production, which drives the differentiation of inflammatory monocytes into Mo-DCs. Further, this delayed differentiation of Mo-DCs in MR1−/− mice was responsible for the delayed recruitment of activated CD4+ T cells to the lungs. These findings establish a novel mechanism by which MAIT cells function to promote both innate and adaptive immune responses.

Factors Influencing Reconstitution of Mucosal-Associated Invariant T Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3918-3918
Author(s):  
Abir Bhattacharyya ◽  
David Fredricks ◽  
Sujatha Srinivasan ◽  
Martin T Morgan ◽  
Michael Boeckh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Stem Cell ◽  
High Throughput ◽  
Gene Sequencing ◽  
Tcr Signaling ◽  
Hematopoietic Stem ◽  
Mait Cells ◽  
Stool Samples ◽  
Mait Cell

Abstract Background: Mucosal-associated invariant T (MAIT) cells are innate-like T cells characterized by high expression of CD161 and a semi-invariant T cell receptor (TCR) comprised of a Vα7.2-Jα33 alpha chain and a limited Vβ repertoire that enables their activation by riboflavin metabolites produced by distinct bacterial and fungal species. MAIT cells are infrequent in cord blood, but undergo TCR-dependent accumulation in neonates in response to gastrointestinal (GI) commensal colonization to comprise approximately 10% of T cells in adult blood. The GI localization of MAIT cells, their capacity to secrete IL-17, and their activation by microbial metabolites suggests a role in mucosal immunity that may be particularly important after allogeneic hematopoietic stem cell transplantation (HCT) when the GI mucosal barrier is compromised and adaptive immunity is impaired. After HCT, the composition of the GI microbiota may be modified by antibiotics, mucositis and immunosuppression, yet its impact on MAIT cell reconstitution, function and post-transplant immunity remain unknown. Aims: To characterize and identify factors influencing MAIT cell reconstitution and function after HCT. Methods: Blood and stool samples were collected from healthy donors and HCT patients prior to and at distinct times after HCT. Absolute counts of MAIT cells, identified as CD3+/CD161hi/Vα7.2+events, were determined in peripheral blood using flow cytometry performed in conjunction with a complete blood count. The bacterial composition of stool was characterized using bacterial 16S rRNA gene PCR with high throughput sequencing and phylogenetic assignment of the amplified fragments. TCR signaling pathway activation in MAIT cells and conventional T cells was evaluated using flow cytometry analysis of phosphoprotein expression after stimulation through the TCR-CD3 complex with anti-CD3/anti-CD28 monoclonal antibodies. TCR Vβ repertoire assessment was performed using high throughput TCRBV gene sequencing. Results: High throughput TCRBV gene sequencing showed that MAIT cells from different donors (n = 3) shared TCRBV sequences, consistent with their capacity to be activated by common GI microbial TCR ligands. Despite GI microbial colonization, MAIT cells from adult donor blood were quiescent and did not proliferate to TCR stimulation. Phosphoprotein flow cytometry established that phosphorylation of proximal TCR signaling pathway molecules (CD3ζ, Lck, and ZAP-70) was diminished and responsible for impaired TCR signaling in adult MAIT cells compared to conventional αβ T cells. MAIT cell proliferation was restored by TCR stimulation in the presence of IL-1β, IL-12, IL-18 and IL-23, raising the possibility that the post-HCT inflammatory environment might be permissive for MAIT cell proliferation driven by GI microbial TCR ligands. We examined the kinetics of MAIT cell reconstitution in HCT patients (n = 163). MAIT cell numbers were lower in patients before conditioning compared to healthy individuals, and were further depleted on the day of stem cell infusion; however, they proliferated in the post-HCT environment in association with induction of Ki67 expression and reached a plateau after day 30 post-HCT (healthy, 56.8/μL; day 30, 6.7/μL). MAIT cell reconstitution after peripheral blood stem cell (PBSC) transplantation was similar comparing myeloablative (MA) and reduced intensity conditioning (RIC) regimens and related compared to unrelated donors, but was highly variable between individuals. Short tandem repeat PCR chimerism studies showed that MAIT cells were of donor origin early after MA and RIC PBSC transplantation. MAIT cell reconstitution was markedly impaired in recipients of cord blood, which contains few MAIT cells, compared to those receiving PBSC, in which MAIT cells are plentiful, suggesting that early MAIT cell reconstitution is primarily derived from mature cells transferred with the HCT graft. Analysis of stool samples from HCT recipients (n = 17) has shown that the relative abundance of distinct gut bacterial species is highly variable between recipients and changed during the course of HCT. Analyses of the relationship between the microbiota and MAIT cell reconstitution will be presented. Conclusions: MAIT cell recovery following HCT varies between different types of transplants and may be influenced by the transferred graft source, the post-HCT environment, and the gut microbiome. Disclosures No relevant conflicts of interest to declare.

scholarly journals MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren J. Howson ◽  
Giorgio Napolitani ◽  
Dawn Shepherd ◽  
Hemza Ghadbane ◽  
Prathiba Kurupati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Mait Cells ◽  
Vaccination Strategies ◽  
Human Volunteers ◽  
Tcr Repertoire ◽  
Cell Clonal Expansion ◽  
Mait Cell

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

Evolution of the Functional Profile of HIV-Specific CD8+ T Cells in Patients With Different Progression of HIV Infection Over 4 Years

2010 ◽  
Vol 55 (1) ◽  
pp. 29-38 ◽  
Author(s):  
Alejandra Peris-Pertusa ◽  
Mariola López ◽  
Norma I Rallón ◽  
Clara Restrepo ◽  
Vincent Soriano ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Functional Profile

scholarly journals T-cell death by apoptosis in vertically human immunodeficiency virus- infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

Blood ◽  
1995 ◽  
Vol 86 (4) ◽  
pp. 1400-1407 ◽  
Author(s):  
RP Lauener ◽  
S Huttner ◽  
M Buisson ◽  
JP Hossle ◽  
M Albisetti ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Interleukin 2 ◽  
Herpes Viruses ◽  
Interleukin 2 Receptor ◽  
Hla Dr ◽  
Immunodeficiency Virus

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV- infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV- infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.

scholarly journals Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection

2010 ◽  
Vol 84 (22) ◽  
pp. 12082-12086 ◽  
Author(s):  
Shannon M. Murray ◽  
Carrie M. Down ◽  
David R. Boulware ◽  
William M. Stauffer ◽  
Winston P. Cavert ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Immune Activation ◽  
Hiv Disease ◽  
Activated T Cells ◽  
Ki 67 ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Highly Correlated ◽  
Chronic Hiv Infection

ABSTRACT Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

scholarly journals Persistent deficiency of mucosa-associated invariant T (MAIT) cells during alcohol-related liver disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yujue Zhang ◽  
Yuanyuan Fan ◽  
Wei He ◽  
Yi Han ◽  
Huarui Bao ◽  
...  
Keyword(s):  
Liver Disease ◽  
Inflammatory Diseases ◽  
Alcoholic Cirrhosis ◽  
Serum Levels ◽  
Pathological Feature ◽  
Alcoholic Fatty Liver ◽  
Functional Changes ◽  
Mait Cells ◽  
Related Liver Disease ◽  
Mait Cell

Abstract Background Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases. Inflammatory response is a basic pathological feature of ALD. Mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the changes of MAIT cell in ALD remains unclear. Results In this study, the levels of MAIT cell were significantly decreased in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction of circulating MAIT cells was correlated with liver function in patients with cirrhosis. Functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. Conclusions Our findings indicate persistent MAIT cell loss during alcohol-related liver disease and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD.

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