MAIT cells are imprinted by the microbiota in early life and promote tissue repair

Constantinides, Michael G.; Link, Verena M.; Tamoutounour, Samira; Wong, Andrea C.; Pérez-Chaparro, Paula Juliana; Han, Seong-Ji; Chen, Y. Erin; Li, Kelin; Farhat, Sepideh; Weckel, Antonin; Krishnamurthy, Siddharth R.; Vujkovic-Cvijin, Ivan; Linehan, Jonathan L.; Bouladoux, Nicolas; Merrill, Eric Dean; Roy, Sudip; Daniel, J.; Adams, Erin J.; Bhandoola, Avinash; Scharschmidt, Tiffany C.; Aubé, Jeffrey; Fischbach, Michael A.; Belkaid, Yasmine

doi:10.1126/science.aax6624

Cited by 394 publications

(483 citation statements)

References 79 publications

(100 reference statements)

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“…Levels of some cytokines may take up to 3–4 months after delivery to normalize, 33 whereas certain immune cell types appear to normalize within 6 weeks 34 . The importance of early exposure to microbiota for MAIT cell development has been recently shown 35 and may explain some of the variation in MAIT cell frequencies in our study population.…”

Section: Discussionmentioning

confidence: 77%

Changes in the Vα7.2+ CD161++ MAIT cell compartment in early pregnancy are associated with preterm birth in HIV‐positive women

Ravi

Chan

Akoto

et al. 2020

American J Rep Immunol

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Problem Human immunodeficiency virus (HIV) infection is associated with an increased risk of adverse pregnancy outcomes, including preterm birth (PTB), despite viral suppression with antiretroviral therapy. Mucosal‐associated invariant T (MAIT) cells are an immune cell subset involved in antimicrobial immunity at mucosal surfaces. MAIT cells have been found at the maternal‐foetal interface, and MAIT cells are typically depleted early in HIV infection. We aimed to investigate changes in MAIT cells in relation to maternal HIV/ART status and PTB. Method of Study We conducted flow cytometric analysis of peripheral blood samples from 47 HIV‐positive (HIV+) and 45 HIV‐negative (HIV−) pregnant women enrolled in a prospective pregnancy cohort study in Soweto, South Africa. Frequencies of Vα7.2+ CD161++ MAIT cells and proportions of CD4+, CD8+ and double‐negative MAIT cells were compared between women with and without HIV infection, and between women with and without PTB or spontaneous preterm labour (Sp‐PTL). Results Although overall MAIT cell frequencies were the same between HIV+ and HIV− patients, HIV+ patients had a higher proportion of CD8+ MAIT cells in the first two trimesters. Women with PTB and Sp‐PTL also had a higher proportion of CD8+ MAIT cells in the first trimester compared to women without these outcomes. The association between changes in MAIT cell subsets and PTB/Sp‐PTL was present in both HIV+ and HIV− women, and an additive effect on MAIT cell subsets was seen in women with both HIV infection and PTB. Conclusions Interactions between HIV‐related and pregnancy‐related changes in MAIT cell subsets and distribution may lead to imbalances in peripheral MAIT cell subsets in early pregnancy. This may contribute to the increased risk of PTB in HIV+ patients by altering the overall functionality of the peripheral MAIT cell compartment.

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Section: Discussionmentioning

confidence: 77%

Changes in the Vα7.2+ CD161++ MAIT cell compartment in early pregnancy are associated with preterm birth in HIV‐positive women

Ravi

Chan

Akoto

et al. 2020

American J Rep Immunol

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“…Indeed, we recently showed that MAIT cells can respond to a variety of microbiome-related bacteria (Tastan et al, 2018) and that they potentially function to tune or sense the microbial ecosystem throughout mucosal tissues. Two recent papers also show that MAIT cell development and expansion is also directly dependent on the microbiome (Constantinides et al, 2019;Legoux et al, 2019;Oh and Unutmaz, 2019). In one paper, the authors show that CD4-CD8- (double negative, or DN) MAIT cells are a functionally distinct subset that migrate to the skin in mice and are potentially involved in tissue repair (Dias et al, 2018;Constantinides et al, 2019;Oh and Unutmaz, 2019).…”

Section: Discussionmentioning

confidence: 95%

“…Two recent papers also show that MAIT cell development and expansion is also directly dependent on the microbiome (Constantinides et al, 2019;Legoux et al, 2019;Oh and Unutmaz, 2019). In one paper, the authors show that CD4-CD8- (double negative, or DN) MAIT cells are a functionally distinct subset that migrate to the skin in mice and are potentially involved in tissue repair (Dias et al, 2018;Constantinides et al, 2019;Oh and Unutmaz, 2019). Thus, it is interesting to note that we observed differences in CD8+ but not in DN MAIT cells in ME/CFS subjects, suggesting that these are different lineages or subsets.…”

Section: Discussionmentioning

confidence: 95%

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Karhan

Ravanmehr

et al. 2019

Preprint

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

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“…Exhibiting characteristics of both innate and adaptive immunity, innate-like T lymphocytes such as iNKT cells, MAIT cells, and subsets of gd T cells, have emerged as key players in the control of immunity and tissue homeostasis [46][47][48][49] . In striking contrast to Tconv cells, which exit the thymus changes driving progression from one cellular state to the next is lacking.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

Krovi

Zhang

Michaels-Foster

et al. 2020

Preprint

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Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT cells using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of their maturation, function, and fate decision in steady state. We identified Hivep3, a zinc finger transcription factor and adaptor protein, as a key factor that is expressed in early precursors and regulates the postselection proliferative burst, differentiation and functions of iNKT cells. Importantly, we extended these results to other PLZF + innate-like T cell populations, highlighting the unique and common requirement of Hivep3 to the development of all innate-like T cells.

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MAIT cells are imprinted by the microbiota in early life and promote tissue repair

Cited by 394 publications

References 79 publications

Changes in the Vα7.2+ CD161++ MAIT cell compartment in early pregnancy are associated with preterm birth in HIV‐positive women

Changes in the Vα7.2+ CD161++ MAIT cell compartment in early pregnancy are associated with preterm birth in HIV‐positive women

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

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