scholarly journals Preserved MAIT cell numbers and function in idiopathic CD4 lymphocytopenia

2020 ◽  
Author(s):  
Ornella Sortino ◽  
Joana Dias ◽  
Megan Anderson ◽  
Elizabeth Laidlaw ◽  
Edwin Leeansyah ◽  
...  
Keyword(s):  
T Cells ◽  
Opportunistic Infections ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Effector Functions ◽  
Mait Cells ◽  
Cell Counts ◽  
Idiopathic Cd4 Lymphocytopenia ◽  
And Function ◽  
Mait Cell

Abstract Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T-cells involved in antimicrobial responses as well as inflammatory, allergic and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells. Herein, we investigate the MAIT cells in patients with idiopathic CD4 + lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections. The numbers, phenotype and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Furthermore, administration of IL-7 to ICL patients expanded the CD8 + MAIT cell subset, with maintained responsiveness and effector functions after IL-7 treatment. In conclusion, ICL patients maintain normal levels and function of MAIT cells preserving some antibacterial responses despite the deficiency in CD4 + T cells.

scholarly journals MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

2020 ◽  
Vol 11 ◽  
Author(s):  
Ali Amini ◽  
Declan Pang ◽  
Carl-Philipp Hackstein ◽  
Paul Klenerman
Keyword(s):  
T Cells ◽  
Environmental Factors ◽  
Immune Cells ◽  
Cell Biology ◽  
Effector Functions ◽  
Mait Cells ◽  
Health And Disease ◽  
And Function ◽  
Barrier Tissues ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease.

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 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.

scholarly journals Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 287-294 ◽  
Author(s):  
Dimitrios I. Zonios ◽  
Judith Falloon ◽  
John E. Bennett ◽  
Pamela A. Shaw ◽  
Doreen Chaitt ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
T Cell ◽  
Natural History ◽  
Opportunistic Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Opportunistic Infections ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Idiopathic Cd4 Lymphocytopenia

AbstractIdiopathic CD4+ lymphocytopenia (ICL) is a rare non–HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm3 throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were “AIDS-defining clinical conditions,” and 4 (11.1%) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm3) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively). This trial is registered at http://clinicaltrials.gov as #NCT00001319.

scholarly journals IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

2020 ◽  
Vol 21 (18) ◽  
pp. 6966
Author(s):  
Heather M. Ren ◽  
Aron E. Lukacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Persistent Infection ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Persistent Infections ◽  
Follicular Helper ◽  
And Function

CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection and cancer by mitigating generation of exhausted T cells (TEX). CD4 T cell help is also required for establishing and maintaining tissue-resident memory T cells (TRM), the nonrecirculating memory T cell subset parked in nonlymphoid tissues to provide frontline defense against reinvading pathogens. Interleukin (IL)-21 is the signature cytokine secreted by follicular helper CD4 T cells (TFH) to drive B cell expansion and differentiation in germinal centers to mount high-affinity, isotype class-switched antibodies. In several infection models, IL-21 has been identified as the CD4 T help needed for formation and survival of TRM and TEX. In this review, we will explore the different memory subsets of CD8 T cells in persistent infections, the metabolic profiles associated with each, and evidence documenting the importance of CD4 T cell-derived IL-21 in regulating CD8 TRM and TEX development, homeostasis, and function.

Neopterin as a predictive marker for disease progression in human immunodeficiency virus type 1 infection.

1989 ◽  
Vol 35 (8) ◽  
pp. 1746-1749 ◽  
Author(s):  
D Fuchs ◽  
T J Spira ◽  
A Hausen ◽  
G Reibnegger ◽  
E R Werner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Macrophage Activation ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Progression Rate ◽  
Cell Counts ◽  
Urinary Neopterin ◽  
Hiv 1

Abstract We assessed the value of urinary neopterin concentrations for prognosis of disease progression in HIV-1-infected patients. Sixty-eight anti-HIV-1 seropositive homosexuals with lymphadenopathy syndrome were tested for urinary neopterin and T-cell subset counts in 1982-83, and the incidence rate at which they developed acquired immunodeficiency syndrome (AIDS) between then and May 1988 was evaluated. Overall, 21 of 68 (30.9%) cases progressed to AIDS, with a yearly progression rate of 4-9%. The predictive value of urinary neopterin concentrations was higher (P = 0.0042) than that of CD4+ T-cell counts (P = 0.015) or the CD4+/CD8+ T-cell ratio (P = 0.022). Counts of CD8+ T-cells failed to show predictive significance (P = 0.29). Similarly, multivariate-regression analysis indicated that neopterin concentrations and CD4+ T-cell numbers were significant copredictors. Produced by human macrophages activated by interferon gamma, neopterin is thus a marker of macrophage activation via T cells. We conclude that these data demonstrate a correlation between the amount of T-cell-macrophage activation, as measured by urinary neopterin concentrations, and the progression of the disease.

scholarly journals Impact of Intestinal Microbiota on Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3393-3393 ◽  
Author(s):  
Alyssa Sheih ◽  
Jonathan L. Golob ◽  
Abir Bhattacharyya ◽  
Michael C. Wu ◽  
Aesha Vakil ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Board Of Directors ◽  
Relative Abundance ◽  
Bacterial Species ◽  
Advisory Committees ◽  
Mait Cells ◽  
Cell Counts ◽  
Increased Risk ◽  
Mait Cell

Abstract INTRODUCTION: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant T cell receptor (TCR) consisting of a Vα7.2 chain paired with a restricted repertoire of Vβ chains. The MAIT cell TCR recognizes riboflavin metabolites, and potentially other ligands produced by distinct bacterial and fungal species and presented in the context of the MHC class I-related molecule (MR1). MAIT cells are abundant in humans, comprising up to 10% of T cells in the peripheral blood, and are enriched in the gastrointestinal (GI) mucosa and liver. The GI localization of MAIT cells and their activation by microbial metabolites raises the possibility of a role in acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT) when the GI mucosal barrier is compromised. Indeed, we found an increased risk of severe aGVHD in patients with low MAIT cell counts in the blood after HCT (Bhattacharyya, BBMT 2018). The impact of alterations in the GI microbiota on reconstitution and function of MAIT cells in HCT recipients remains unknown. METHODS: Paired blood and stool samples were collected from allogeneic HCT recipients prior to conditioning, and on days 0, 10, 20, 30, 60, and 100 after HCT. MAIT cells were identified as CD3+/CD161hi/Vα7.2+ cells by flow cytometry and absolute counts in the peripheral blood were determined in conjunction with a complete blood count. The bacterial composition of the stool was characterized by broad-range 16S ribosomal RNA gene PCR and high-throughput sequencing followed by placement into a maximum-likelihood phylogeny via pplacer against a custom reference package. A linear mixed model with random intercept was used to estimate the correlation between absolute MAIT cell count in the blood and relative abundance of bacterial species in the stool. RESULTS: We analyzed 302 paired blood and stool samples from 78 allogeneic HCT recipients. MAIT cells declined from pre-conditioning levels to a nadir on the day of stem cell infusion, followed by an increase to a plateau between day 30 and 100 after HCT. Microbial diversity was low prior to HCT and further decreased in the first 20 days after HCT, followed by an increase between days 30 and 100 to pre-HCT levels. MAIT cell counts in the blood correlated with stool microbial diversity and the relative abundance of individual bacterial species. We found a direct correlation between the abundance of bacterial species belonging to the Lachnospiraceae family (including distinct Blautia and Clostridium spp.) and an inverse correlation between the relative abundance of oral and perineal bacteria in the stool with absolute MAIT cell counts in blood (Table 1). Consistent with our findings and a possible protective role for MAIT cells in the pathogenesis of aGVHD (Varelias, JCI 2018), decreased Blautia abundance in stool has been associated with increased risk of death from aGVHD (Jenq, BBMT 2015) and increased abundance of oral and perineal bacteria in stool has been associated with aGVHD (Golob, CID 2017). CONCLUSION: In this study, we identified bacterial species whose relative abundance directly or inversely correlated with the absolute number of MAIT cells in blood after HCT. This observation is consistent with a mechanism in which a gut microbiome that is deficient in bacteria in the Lachnospiraceae family (capable of generating riboflavin metabolites for MAIT cell activation) is associated with poor MAIT cell recovery and potentially an increased risk of aGVHD. Disclosures Turtle: Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Changes in the regulatory T-lymphocyte counts in HIV-infected patients with a discordant response to antiretroviral therapy

2019 ◽  
Vol 487 (5) ◽  
pp. 584-587
Author(s):  
E. V. Saidakova ◽  
K. V. Shmagel ◽  
N. G. Shmagel ◽  
L. B. Korolevskaya ◽  
V. A. Chereshnev
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Treg Frequency ◽  
Cell Counts ◽  
High Viability ◽  
System Restoration ◽  
Regulatory T Lymphocyte

We examined HIV‑infected patients with different efficiency of immune system restoration during the course of antiretroviral therapy. The study showed that against the background of low CD4+ T‑cell counts, subject with a discordant immunologic response (patients with less than 350 CD4+ T‑cells per µl of blood after more than two years of treatment) develop a regulatory CD4+ T‑cell (Treg) deficiency. Furthermore, in these patients, the immunodeficiency is accompanied by an increase in the Treg frequency. Accumulation of regulatory T‑cells in the blood of HIV‑infected subjects with discordant response to the treatment indicates a high viability of this T‑cell subset.

scholarly journals Mucosal-Associated Invariant T (MAIT) Cell Dysfunction and PD-1 Expression in Prostate Cancer: Implications for Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Ellie-May Jarvis ◽  
Shaun Collings ◽  
Astrid Authier-Hall ◽  
Nathaniel Dasyam ◽  
Brendan Luey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Dependent Manner ◽  
Mait Cells ◽  
Cell Dysfunction ◽  
And Function ◽  
Mait Cell

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells. MAIT cells express stereotyped T-cell receptors that recognize riboflavin metabolites derived from microbes presented by MR-1. We evaluated the number, phenotype and function of circulating MAIT cells, alongside two other innate-like T (ILT) -cell subsets, in men with prostate cancer and age- and sex-matched controls. MAIT cells in men with prostate cancer circulated at similar frequencies to controls, but their cytokine production and proliferation was impaired. In contrast, the function of two other ILT-cell populations (natural killer T-cells and Vγ9Vδ2 T-cells) was not impaired. In both patients and controls, MAIT cells expressed high levels of the immune checkpoint molecule PD-1 at rest, while upregulation of PD-1 in response to the MR-1 ligand 5-amino-6D-ribitylaminouracil (5-A-RU) was greater in patients. 5-A-RU also induced upregulation of PD-L1 and -L2 RNA in primary mononuclear cells. We confirmed that circulating MAIT cell number and function were preserved before and during anti-PD1 therapy with pembrolizumab in a cohort of patients with melanoma. In vitro, 5-A-RU enhanced mononuclear cell cytotoxicity against the PD-L1 positive prostate cancer cell line PC3 in an MR-1-dependent manner. Addition of pembrolizumab enhanced this cytotoxicity, and was associated with increased MAIT cell expression of CD107a and IFN-γ. We conclude that prostate cancer is associated with MAIT-cell dysfunction, and that this might be overcome through the application of potent MR-1 ligands with PD-1 blockade. These findings may have implications for the development of cancer immunotherapies that exploit MAIT cells.

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