Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent ...adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8
T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.
Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are innate-like T cells that function at the interface between innate and adaptive immunity. They express ...semi-invariant T cell receptors (TCRs) and recognize unconventional non-peptide ligands bound to the MHC Class I-like molecules MR1 and CD1d, respectively. MAIT cells and iNKT cells exhibit an effector-memory phenotype and are enriched within the liver and at mucosal sites. In humans, MAIT cell frequencies dwarf those of iNKT cells, while in laboratory mouse strains the opposite is true. Upon activation
TCR- or cytokine-dependent pathways, MAIT cells and iNKT cells rapidly produce cytokines and show direct cytotoxic activity. Consequently, they are essential for effective immunity, and alterations in their frequency and function are associated with numerous infectious, inflammatory, and malignant diseases. Due to their abundance in mice and the earlier development of reagents, iNKT cells have been more extensively studied than MAIT cells. This has led to the routine use of iNKT cells as a reference population for the study of MAIT cells, and such an approach has proven very fruitful. However, MAIT cells and iNKT cells show important phenotypic, functional, and developmental differences that are often overlooked. With the recent availability of new tools, most importantly MR1 tetramers, it is now possible to directly study MAIT cells to understand their biology. Therefore, it is timely to compare the phenotype, development, and function of MAIT cells and iNKT cells. In this review, we highlight key areas where MAIT cells show similarity or difference to iNKT cells. In addition, we discuss important avenues for future research within the MAIT cell field, especially where comparison to iNKT cells has proven less informative.
Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to ...local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.
Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal TRM cells remains ...undefined. Here, we investigate transcriptional and functional heterogeneity of human TRM cells through study of donor-derived TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8+ TRM phenotypes. CD8+ CD69+CD103+ TRM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin+CD69+CD103− TRM cells have higher granzyme expression. Analysis of intestinal CD4+ T cells identifies several parallels, including a β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
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•Human intestinal transplants were used to identify bona fide TRM cells•Single-cell RNA sequencing identifies two distinct CD8+ TRM subsets•CD103+CD69+ and CD103−CD69+ TRM cell subsets show distinct localization and function•β2-integrin is highly expressed on CD103− TRM cells
It has been historically difficult to accurately identify human tissue-resident memory T (TRM) cells. FitzPatrick et al. use a model of human intestinal transplantation to more definitively identify human TRM cells. Single-cell RNA sequencing reveals two transcriptionally distinct populations of intestinal CD8+ TRM cells, which show differences in localization and function.
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of ...human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.
Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the ...capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2
versus Vδ1
γδT cells to the observation that Vδ2
γδT cells, but not Vδ1
γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161
and CD161
Vδ2
γδT cells responded to these stimuli, with increased functionality within the CD161
subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2
γδT cells in human duodenum and liver maintained a CD161
IL-18Rα
phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2
γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2
γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2
γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells.
Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the ...human germinal center response. However, systematic deep phenotyping of the cellular populations and cell‐free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof‐of‐concept and used single‐cell RNA‐sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone‐fide LN‐resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood‐derived populations. LN FNA supernatants represent a specific source of lymph‐ and lymph node‐derived proteins, and can, aided by transcriptomics, identify likely receptor–ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell‐free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.
Lymph node fine needle aspiration is a powerful technique for sampling human lymphoid tissue. However, it has not been used to study innate immune populations or lymph node‐associated soluble factors. Using single‐cell RNA‐sequencing and proteomics, we demonstrate the ability of this technique to elucidate the unique biology of these immune parameters.
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine ...whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.
Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort,
= 566) and verification (PETACC3 clinical trial,
= 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes
and
), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.
Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of
, the alpha subunit of the heterodimeric IL22 receptor, and
mutation relapse-free survival (RFS): HR = 2.93,
= 0.0006; overall survival (OS): HR = 2.45,
= 0.0023.
mutations showed a similar interaction with
and conferred the worst prognosis in tumors with high expression of both
and
(RFS: HR = 3.81,
= 0.0036; OS: HR = 3.90,
= 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in
mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.
Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.
An atlas of cells in the human tonsil Massoni-Badosa, Ramon; Aguilar-Fernández, Sergio; Nieto, Juan C. ...
Immunity (Cambridge, Mass.),
02/2024, Letnik:
57, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of ...>556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.
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•Single-cell atlas of the human tonsils as a model for secondary lymphoid organs•Comprehensive glossary of 121 cell types and states defined by multimodal profiling•High-resolution immune cell activation landscape with lineage-defining regulators•A FAIR resource accessible through HCATonsilData
Massoni-Badosa et al. present a comprehensive human tonsil cell atlas, identifying 121 cell types and states through multimodal single-cell profiling. This atlas elucidates cell differentiation pathways and regulatory circuits, defines cell states, and provides a reference for annotating immune cell types and characterizing phenotypic plasticity in pathological settings such as lymphoid neoplasms.
Vδ2+ γδT cells are unconventional T cells that can be activated by cytokines without TCR signaling. Adenovirus vaccine vectors activated Vδ2+ γδT cells in an interleukin 18‐, TNF‐, and type I ...interferon‐dependent manner. This stimulatory capacity was associated with adenovirus vectors of non‐species C origin, including the ChAdOx1 vaccine platform.
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