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

Science ◽  
2019 ◽  
Vol 366 (6464) ◽  
pp. 494-499 ◽  
Author(s):  
François Legoux ◽  
Déborah Bellet ◽  
Celine Daviaud ◽  
Yara El Morr ◽  
Aurelie Darbois ◽  
...  
Keyword(s):  
T Cells ◽  
Orphan Receptor ◽  
Immune Functions ◽  
Thymic Development ◽  
Germ Free ◽  
Mait Cells ◽  
Histocompatibility Complex ◽  
Mucosal Surfaces ◽  
Mucosal Homeostasis ◽  
Antigen 5

How the microbiota modulate immune functions remains poorly understood. Mucosal-associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic development, as MAIT cells did not recirculate to the thymus. MAIT development required RibD expression in bacteria, indicating that production of the MAIT antigen 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) was necessary. 5-OP-RU rapidly traveled from mucosal surfaces to the thymus, where it was captured by the major histocompatibility complex class Ib molecule MR1. This led to increased numbers of the earliest MAIT precursors and the expansion of more mature receptor-related, orphan receptor γt–positive MAIT cells. Thus, a microbiota-derived metabolite controls the development of mucosally targeted T cells in a process blurring the distinction between exogenous antigens and self-antigens.

scholarly journals Peripheral Blood Mucosal-Associated Invariant T Cells in Tuberculosis Patients and Healthy Mycobacterium tuberculosis-Exposed Controls

2020 ◽  
Vol 222 (6) ◽  
pp. 995-1007 ◽  
Author(s):  
Sara Suliman ◽  
Anele Gela ◽  
Simon C Mendelsohn ◽  
Sarah K Iwany ◽  
Kattya Lopez Tamara ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Major Histocompatibility Complex ◽  
Cell Receptor ◽  
Surface Markers ◽  
Strongly Correlated ◽  
Major Histocompatibility ◽  
Mait Cells ◽  
Histocompatibility Complex ◽  
Variable Gene

Abstract Background In human blood, mucosal-associated invariant T (MAIT) cells are abundant T cells that recognize antigens presented on non-polymorphic major histocompatibility complex-related 1 (MR1) molecules. The MAIT cells are activated by mycobacteria, and prior human studies indicate that blood frequencies of MAIT cells, defined by cell surface markers, decline during tuberculosis (TB) disease, consistent with redistribution to the lungs. Methods We tested whether frequencies of blood MAIT cells were altered in patients with TB disease relative to healthy Mycobacterium tuberculosis-exposed controls from Peru and South Africa. We quantified their frequencies using MR1 tetramers loaded with 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. Results Unlike findings from prior studies, frequencies of blood MAIT cells were similar among patients with TB disease and latent and uninfected controls. In both cohorts, frequencies of MAIT cells defined by MR1-tetramer staining and coexpression of CD161 and the T-cell receptor alpha variable gene TRAV1-2 were strongly correlated. Disease severity captured by body mass index or TB disease transcriptional signatures did not correlate with MAIT cell frequencies in patients with TB. Conclusions Major histocompatibility complex (MHC)-related 1-restrictied MAIT cells are detected at similar levels with tetramers or surface markers. Unlike MHC-restricted T cells, blood frequencies of MAIT cells are poor correlates of TB disease but may play a role in pathophysiology.

scholarly journals Characteristics of mucosal-associated invariant T cells and their roles in immune diseases

2021 ◽  
Author(s):  
Asako Chiba ◽  
Goh Murayama ◽  
Sachiko Miyake
Keyword(s):  
T Cells ◽  
Lupus Erythematosus ◽  
Cell Receptor ◽  
Mait Cells ◽  
Histocompatibility Complex ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Human Immune ◽  
Derivatives Of ◽  
Riboflavin Synthesis

Abstract Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that express a semi-invariant T cell receptor and are restricted by the molecule major histocompatibility complex class I-related molecule 1 (MR1). MAIT cells recognize biosynthetic derivatives of the riboflavin synthesis pathway present in microbes. MAIT cells have attracted increased interest related to various immune responses because of their unique features including their abundance in humans, nonpeptidic antigens, and ability to respond to antigenic and non-antigenic stimuli. The numbers of circulating MAIT cells are decreased in many immune diseases such as multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel diseases. However, the remaining MAIT cells have an increased cytokine-producing capacity and activated status, which is related to disease activity. Additionally, MAIT cells have been observed at sites of inflammation including the kidneys, synovial fluid and intestinal mucosa. These findings suggest their involvement in the pathogenesis of immune diseases. In this mini-review, we summarize the recent findings of MAIT cells in human immune diseases and animal models, and discuss their role and potential as a therapeutic target.

Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge

2020 ◽  
Vol 20 (12) ◽  
pp. 756-770 ◽  
Author(s):  
Daniel G. Pellicci ◽  
Hui-Fern Koay ◽  
Stuart P. Berzins
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Nkt Cells ◽  
Thymic Development ◽  
Mait Cells

scholarly journals Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture.

1993 ◽  
Vol 177 (5) ◽  
pp. 1469-1473 ◽  
Author(s):  
K A Hogquist ◽  
M A Gavin ◽  
M J Bevan
Keyword(s):  
T Cells ◽  
Positive Selection ◽  
Cd8 T Cells ◽  
Class I ◽  
Thymic Development ◽  
Histocompatibility Complex ◽  
Binding Peptides ◽  
Beta 2 ◽  
Selection Of

We have used an in vitro system to study the effects of major histocompatibility complex class I binding peptides on thymic development. Fetal thymus lobes from mice deficient in the class I light chain (beta 2 microglobulin or beta 2 M-/-) were cultured for 10 d in vitro, during which time T cell precursors develop into mature T cells. In these organ cultures, as in the adult or neonatal beta 2 M-/- thymus, CD8+ mature T cells did not develop, demonstrating that the mature T cells seen during early murine thymic development are the result of the positive selection process. To these cultures we added various class I binding peptides with or without a source of exogenous beta 2M. CD8+ T cells developed to various degrees only in the presence of beta 2M and peptides. Using peptide mixtures of differing complexity, we showed that the efficiency of this process is dependent more on peptide complexity than on peptide concentration. These data argue for a specific role for peptides in the process of positive selection. Furthermore, this culture system should be useful in identifying peptides that can promote positive selection of cells expressing a specific T cell receptor (TCR) in TCR transgenic mice.

scholarly journals Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers

2015 ◽  
Vol 212 (7) ◽  
pp. 1095-1108 ◽  
Author(s):  
Azad Rahimpour ◽  
Hui Fern Koay ◽  
Anselm Enders ◽  
Rhiannon Clanchy ◽  
Sidonia B.G. Eckle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptors ◽  
Promyelocytic Leukemia ◽  
Orphan Receptor ◽  
Gm Csf ◽  
Mait Cells ◽  
Specific Manner ◽  
Health And Disease ◽  
Ifn Γ ◽  
Invariant T Cells

Studies on the biology of mucosal-associated invariant T cells (MAIT cells) in mice have been hampered by a lack of specific reagents. Using MR1-antigen (Ag) tetramers that specifically bind to the MR1-restricted MAIT T cell receptors (TCRs), we demonstrate that MAIT cells are detectable in a broad range of tissues in C57BL/6 and BALB/c mice. These cells include CD4−CD8−, CD4−CD8+, and CD4+CD8− subsets, and their frequency varies in a tissue- and strain-specific manner. Mouse MAIT cells have a CD44hiCD62Llo memory phenotype and produce high levels of IL-17A, whereas other cytokines, including IFN-γ, IL-4, IL-10, IL-13, and GM-CSF, are produced at low to moderate levels. Consistent with high IL-17A production, most MAIT cells express high levels of retinoic acid–related orphan receptor γt (RORγt), whereas RORγtlo MAIT cells predominantly express T-bet and produce IFN-γ. Most MAIT cells express the promyelocytic leukemia zinc finger (PLZF) transcription factor, and their development is largely PLZF dependent. These observations contrast with previous reports that MAIT cells from Vα19 TCR transgenic mice are PLZF− and express a naive CD44lo phenotype. Accordingly, MAIT cells from normal mice more closely resemble human MAIT cells than previously appreciated, and this provides the foundation for further investigations of these cells in health and disease.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

Development of Mucosal Immunity: Functional Interactions with Mucosal Microbiome in Health and Disease

2019 ◽  
Vol 15 (2) ◽  
pp. 154-165
Author(s):  
Oscar G. Gómez-Duarte ◽  
Pearay L. Ogra
Keyword(s):  
Adaptive Immunity ◽  
Mucosal Immunity ◽  
Plasma Cells ◽  
External Environment ◽  
Mammalian Host ◽  
Immune Functions ◽  
Principal Mechanism ◽  
Functional Development ◽  
Mucosal Surfaces ◽  
Specific Pathogen

The mucosal surfaces and the skin are the primary sites of interactions between the mammalian host and the external environment. These sites are exposed continuously to the diverse components of the environment, including subcellular, unicellular and multicellular organisms, dietary agents and food products; and numerous other soluble or cellular air or water borne products. The development of innate and adaptive immunity in the mucosal surfaces and the skin are the principal mechanism of mammalian defense evolved to date, in order to maintain effective homeostatic balance between the host and the external environment. The innate immune functions are mediated by a number of host specific Pathogen Recognition Receptors (PRR), designed to recognize unique Pathogen Associated Molecular Patterns (PAMP), essential to the molecular structure of the microorganism. The major components of specific adaptive immunity in the mucosal surfaces include the organized antigen-reactive lymphoid follicles in different inductive mucosal sites and the effector sites of the lamina propria and sub-epithelial regions, which contain lymphoid and plasma cells, derived by the homing of antigen sensitized cells from the inductive sites. The acquisition of environmental microbiome by the neonate in its mucosal surfaces and the skin, which begins before or immediately after birth, has been shown to play a critical and complex role in the development of mucosal immunity. This report provides an overview of the mammalian microbiome and highlights its role in the evolution and functional development of immunologic defenses in the mucosal surface under normal physiologic conditions and during infectious and non-infectious inflammatory pathologic states associated with altered microbiota.

scholarly journals Cryopreservation of Whole Tumor Biopsies from Rectal Cancer Patients Enable Phenotypic and In Vitro Functional Evaluation of Tumor-Infiltrating T Cells

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2428
Author(s):  
Frank Liang ◽  
Azar Rezapour ◽  
Peter Falk ◽  
Eva Angenete ◽  
Ulf Yrlid
Keyword(s):  
Rectal Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Functional Evaluation ◽  
Mait Cells ◽  
Ifn Γ ◽  
Tumor Biopsies

TILs comprise functionally distinct conventional and unconventional T cell subsets and their role in responses to CRC treatments is poorly understood. We explored recovery of viable TILs from cryopreserved tumor biopsies of (chemo)-radiated patients with rectal cancer to establish a platform for retrospective TIL analyses of frozen tumors from pre-selected study cohorts. Frequencies of TIL subsets and their capacity to mount IFN-γ responses in cell suspensions of fresh vs. cryopreserved portions of the same tumor biopsies were determined for platform validation. The percentages and proportions of CD4+ TILs and CD8+ cytotoxic T lymphocytes (CTLs) among total TILs were not affected by cryopreservation. While recovery of unconventional γδ T cells and mucosal-associated invariant T cells (MAIT cells) was stable after cryopreservation, the regulatory T cells (Tregs) were reduced, but in sufficient yields for quantification. IFN-γ production by in vitro-stimulated CD4+ TILs, CTLs, γδ T cells, and MAIT cells were proportionally similar in fresh and cryopreserved tumor portions, albeit the latter displayed lower levels. Thus, the proposed platform intended for TIL analyses on cryopreserved tumor biobank biopsies holds promises for studies linking the quantity and quality of TIL subsets with specific clinical outcome after CRC treatment.

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