Microbial metabolites control the thymic development of mucosal-associated invariant T cells

Legoux, François; Bellet, Déborah; Daviaud, Céline; Morr, Yara El; Darbois, Aurélie; Niort, Kristina; Procopio, Emanuele; Salou, Marion; Gilet, Jules; Ryffel, Bernhard; Balvay, Aurélie; Foussier, Anne; Sarkis, Manal; Marjou, Ahmed El; Schmidt, Frédéric; Rabot, Sylvie; Lantz, Olivier

doi:10.1126/science.aaw2719

Cited by 246 publications

(246 citation statements)

References 33 publications

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“…17 Finally, in a process affecting all mucosal surfaces, it was shown that bacterial metabolites of vitamin B2 are required before weaning to induce the generation of mucosa-associated invariant T (MAIT) cells in the adult. 44,45 The weaning reaction Another twist in the story was added by the characterization of the weaning reaction. We reported that the weaning reaction is the first vigorous immune response to the colonizing intestinal microbiota after birth.…”

Section: A Fetal Time Window?mentioning

confidence: 99%

Imprinting of the immune system by the microbiota early in life

2020

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The ontogeny and maturation of the immune system is modulated by the microbiota. During fetal life, the mother's microbiota produces compounds that are transferred to the fetus and offspring, and enhance the generation of innate immune cells. After birth, the colonizing microbiota induces the development of intestinal lymphoid tissues and maturation of myeloid and lymphoid cells, and imprints the immune system with a reactivity level that persists long after weaning into adulthood. When the cross-talk between host and microbiota is perturbed early in life, a pathological imprinting may develop that is characterized by excessive immune reactivity in adulthood, which translates into increased susceptibility to inflammatory pathologies. In this review, we discuss the recent data that demonstrate the existence of a time window of opportunity early in life during which mice and human have to be exposed to microbiota in order to develop a balanced immune system. We also discuss the factors involved in imprinting, such as the microbiota, immune cells and stromal cells, as well as the nature of imprinting.Mucosal Immunology (2020) 13:183-189; https://doi.

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Section: A Fetal Time Window?mentioning

confidence: 99%

Imprinting of the immune system by the microbiota early in life

2020

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“…iNKT cells acquire an innate-like effector memory program during thymic development and egress from the thymus expressing the transcription factor promyelocytic leukemia zinc finger (PLZF), which regulates an innate-like phenotype in iNKT and MAIT cells, as well as innate lymphoid and natural killer cells (51)(52)(53). MAIT cells egress from the thymus with a naive surface phenotype and acquire an innate-like effector memory program, including PLZF expression, during expansion in the periphery following microbial colonization (52,54). The development of mycolipid-specific T cells is largely unknown.…”

Section: Mycolipid-specific T Cell Developmentmentioning

confidence: 99%

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

James

Seshadri

2020

Front. Immunol.

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Diseases due to mycobacteria, including tuberculosis, leprosy, and Buruli ulcer, rank among the top causes of death and disability worldwide. Animal studies have revealed the importance of T cells in controlling these infections. However, the specific antigens recognized by T cells that confer protective immunity and their associated functions remain to be definitively established. T cells that respond to mycobacterial peptide antigens exhibit classical features of adaptive immunity and have been well-studied in humans and animal models. Recently, innate-like T cells that recognize lipid and metabolite antigens have also been implicated. Specifically, T cells that recognize mycobacterial glycolipid antigens (mycolipids) have been shown to confer protection to tuberculosis in animal models and share some biological characteristics with adaptive and innate-like T cells. Here, we review the existing data suggesting that mycolipid-specific T cells exist on a spectrum of "innateness," which will influence how they can be leveraged to develop new diagnostics and vaccines for mycobacterial diseases.

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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%

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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Microbial metabolites control the thymic development of mucosal-associated invariant T cells

Cited by 246 publications

References 33 publications

Imprinting of the immune system by the microbiota early in life

Imprinting of the immune system by the microbiota early in life

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

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

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