HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161++CD8+ T cells are a tissue-infiltrating population that produce IL17A, ...IL22, IFNγ, and TNFα, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR Vα7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function of CD161++/MAIT cells in peripheral blood and tissue from patients with early stage or chronic-stage HIV infection. We show that the CD161++/MAIT cell population is significantly decreased in early HIV infection and fails to recover despite otherwise successful treatment. We provide evidence that CD161++/MAIT cells are not preferentially infected but may be depleted through diverse mechanisms including accumulation in tissues and activation-induced cell death. This loss may impact mucosal defense and could be important in susceptibility to specific opportunistic infections in HIV.
•The frequency of CD161++ MAIT cells is dramatically decreased in the blood of HIV-infected patients, and they are nonrecoverable with HAART.•Gut sequestration and apoptosis in response to bacterial signals may, amongst others, be mechanisms that contribute to this.
The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether ...different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.
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•CD161 expression defines specific T cell subsets, including CD8+, CD4+, and TCRγδ+•CD161-expressing lymphocytes possess a conserved transcriptional signature•CD161-expressing lymphocytes display a shared innate response to IL-12+18•CD161 can act as a costimulatory receptor
T lymphocytes are conventionally divided into subsets based on expression of coreceptors, cytokines, and surface molecules. Using CyTOF and mRNA microarray analysis, Fergusson et al. identify T lymphocytes that express the C-type lectin CD161 to share a transcriptional profile and innate function across these previously defined subsets.
Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their ...expression of Vα7.2-Jα33/Jα20/Jα12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ Vα7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ Vα7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ Vα7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ Vα7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ Vα7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ Vα7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ Vα7.2+ T cells and indicate potentially distinct roles for the different subsets
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Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. ...Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.
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•Comprehensive profiling of human ILCs across tissues•Detailed description of previously defined ILC subsets except helper-type ILC1•ieILC1-like cells are present in several tissues and functionally similar to NK cells•Identification of markers expressed on ILCs, including functional IL-18R
Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. Simoni et al. (2016) profile human ILCs using mass cytometry across tissues. The results provide a global, comprehensive, and detailed description of ILC populations and their heterogeneity across individuals and tissues.
CD161-expressing human T cells Fergusson, Joannah R; Fleming, Vicki M; Klenerman, Paul
Frontiers in immunology,
01/2011, Letnik:
2
Journal Article
Recenzirano
Odprti dostop
Expression of the Natural Killer cell receptor CD161 has recently been identified on a subset of T cells, including both CD4+ T helper and CD8+ T cells. Expression of this molecule within the adult ...circulation is restricted to those T cells with a memory phenotype. However, the distinct properties of these T cell populations is yet to be fully determined, although expression of CD161 has been related to the secretion of interleukin-17, and therefore to a type 17 phenotype. Recent studies have aimed to determine both the origin of these cells and the significance of CD161 expression as either a marker of specific cell types or as an effector and regulator of lymphocyte function, and hence to characterize the role of these CD161+ cells within a variety of human diseases in which they have been implicated.
Expression of the Autoimmune regulator (AIRE) outside of the thymus has long been suggested in both humans and mice, but the cellular source in humans has remained undefined. Here we identify AIRE ...expression in human tonsils and extensively analyzed these "extra-thymic AIRE expressing cells" (eTACs) using combinations of flow cytometry, CyTOF and single cell RNA-sequencing. We identified AIRE+ cells as dendritic cells (DCs) with a mature and migratory phenotype including high levels of antigen presenting molecules and costimulatory molecules, and specific expression of CD127, CCR7, and PDL1. These cells also possessed the ability to stimulate and re-stimulate T cells and displayed reduced responses to toll-like receptor (TLR) agonists compared to conventional DCs. While expression of
was enriched within CCR7+CD127+ DCs, single-cell RNA sequencing revealed expression of
to be transient, rather than stable, and associated with the differentiation to a mature phenotype. The role of AIRE in central tolerance induction within the thymus is well-established, however our study shows that
expression within the periphery is not associated with an enriched expression of tissue-restricted antigens (TRAs). This unexpected finding, suggestive of wider functions of AIRE, may provide an explanation for the non-autoimmune symptoms of APECED patients who lack functional AIRE.
Background and Aims
Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV‐specific immune ...responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity‐enhanced T Cell receptor with an anti‐CD3 T Cell‐activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus‐derived peptides presented by human leukocyte antigen (HLA).
Approach and Results
ImmTAV molecules specific for HLA‐A*02:01‐restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV‐Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging‐based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV‐Env can redirect T cells from healthy and HBV‐infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV‐Env redirection of T cells induced cytolysis of antigen‐positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA.
Conclusions
The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non‐HBV‐specific T cells, bypassing exhausted HBV‐specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.
Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high ...polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the
gene of
(Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial
as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.
Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for ...global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%-100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different T
1/T
2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design.
Discovered 30 years ago, gamma delta (γδ) T-lymphocytes remain an intriguing and enigmatic T-cell subset. Although in humans they comprise a small fraction of the total circulating T-lymphocyte pool, ...they represent an important T-cell subset in tissues such as the liver, with roles bridging the innate and adaptive immune systems. The associations of γδ T-lymphocytes with chronic liver disease have been explored - however, there remain conflicting data as to whether these T-cells are pathogenic or protective. In patients with some forms of liver disease, their expansion in the periphery and especially in the liver may indeed help pathogen clearance, while in other conditions their presence may, in contrast, contribute to disease progression. γδ T-cells can also express CD161, a C-type lectin, and such cells have been found to be involved in the pathogenesis of inflammatory disease. CD161+ T-cells of diverse subsets are known to be enriched in the livers of patients with chronic hepatitis C. This article serves to provide a review of the γδ T-cell population and its role in hepatitis C and other chronic liver diseases, and also explores a potential role of the CD161+ γδ T-cells in liver diseases.
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