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A monoclonal Trd chain supports the development of the complete set of functional γδ T cell lineages

ABSTRACT: The clonal selection theory describes the key features of adaptive immune responses of B and T cells. For αβ T cells and B cells antigen recognition and selection principles are known at a detailed molecular level. The precise role of the antigen receptor in γδ T cells remains less well understood. To better understand the role of the γδ T cell receptor (TCR), in particular its specificity for thymic selection of γδ T cells and for γδ T cell biology in general, we generated a novel orthotopic TCRδ transgenic mouse model. We demonstrate a multi-layered functionality of γδ TCRs and diverse roles of CDR3δ-mediated selection during γδ T cell development. Whereas epithelial populations using Vγ5 or Vγ7 chains are affected to only minor extend in their biology in the presence of a single TCRδ chain, pairing with Vγ1 positively selects subpopulations of γδ T cells with distinct programs in several organs, thereby distorting the repertoire. In conclusion, our data support dictation of developmental tropism together with adaptive-like recognition principles in a single antigen receptor.

ORGANISM(S): Mus musculus

PROVIDER: GSE225874 | GEO | 2023/02/24

REPOSITORIES: GEO

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A monoclonal Trd chain supports the development of the complete set of functional γδ T cell lineages (VDJ)

Project description:The clonal selection theory describes the key features of adaptive immune responses of B and T cells. For αβ T cells and B cells antigen recognition and selection principles are known at a detailed molecular level. The precise role of the antigen receptor in γδ T cells remains less well understood. To better understand the role of the γδ T cell receptor (TCR), in particular its specificity for thymic selection of γδ T cells and for γδ T cell biology in general, we generated a novel orthotopic TCRδ transgenic mouse model. We demonstrate a multi-layered functionality of γδ TCRs and diverse roles of CDR3δ-mediated selection during γδ T cell development. Whereas epithelial populations using Vγ5 or Vγ7 chains are affected to only minor extend in their biology in the presence of a single TCRδ chain, pairing with Vγ1 positively selects subpopulations of γδ T cells with distinct programs in several organs, thereby distorting the repertoire. In conclusion, our data support dictation of developmental tropism together with adaptive-like recognition principles in a single antigen receptor.

2023-03-01 | GSE225035 | GEO

A monoclonal Trd chain supports the development of the complete set of functional γδ T cell lineages (NGS)

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γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges

Project description:γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

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MHC class II inhibits the generation of IL-17A+ Vγ6 γδ T cells in the thymus at perinatal stage

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2022-08-01 | GSE180320 | GEO

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Project description:Murine γδ T cells include several effector subsets that fulfil distinct functional roles. In pathological conditions, such as cancer, some γδ T cell subsets are highly protective whereas other subsets may exacerbate disease. γδ T cells are programmed for their effector function during their development in the thymus. Investigations of γδ T cell development have been hampered by the scarcity of surface markers distinguishing different development stages. In this study, we found that addition of CD117, CD200 and CD371 to existing markers, allowed identification of seven distinct development stages (named A, B, C, D, E, F and G) present in both the Vγ1.1+ and Vγ2+ thymocyte subsets. We provide evidence for the existence of three distinct pathways leading to export of γδ T cells, two of which express high levels of CD24. These pathways are dominated by different TCRδ repertoires shaped by TCR signalling or lack thereof. Each pathway express distinct cytokine and transcription factor profiles associated with γδT1, γδNKT and adaptive γδ T cells. Thus, the identification of additional γδ T cell development stages in this study connects three distinct development pathways to the programming of three γδ T cell effector subsets.

2017-10-18 | GSE97137 | GEO

Meningeal γδ T cells producing IL-17 control synaptic plasticity and cognitive behaviour

Project description:The conventional notion of “immune privilege” of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology (Louveau, Trends Immunol 2015; Kipnis science 2016; Filiano, Nat Rev Neurosciences 2017). Surprisingly, such neuroimmune functions have been linked to “pro-inflammatory” cytokines like IL-4 or IFN-α, shown to control behavioural and social cognition (Derecki, JEM 2010; Filiano, Nature 2016). Here we identify a pro-cognitive role for IL-17 in short-term memory that derives from a previously unknown meningeal-resident γδ T cell subset. This was mostly composed of foetal thymic-derived Vγ6+ T cells, found in the meninges at birth and persisting throughout life, where they were strikingly polarized towards IL-17 production. In fact, γδ T cells were the overwhelming source of meningeal IL-17, whereas IFN-γ was mostly provided by T cells. To assess whether the constitutive production of IL-17 by γδ T cells influenced the cognitive performance of mice, we tested TCRδ-/-, IL-17-/- and respective WT littermate control mice in classical learning paradigms. We observed that mice deficient either for γδ T cells or IL-17 displayed impaired short-term memory in the Y maze paradigm, while retaining normal long-term spatial memory in the Morris water maze. A detailed proteomics analysis of the hippocampus provided mechanistic insight into reduced plasticity of the glutamatergic synapses in the absence of IL-17, which associated with impaired Long Term Potentiation (LTP). Conversely, IL-17 enhanced glial cell production of Brain Derived Neurotropic Factor (BDNF), whose exogenous provision rescued the LTP defect of IL-17-/- animals. Altogether, our data demonstrate that foetal-derived γδ T cells populate the brain meninges where they regulate synaptic plasticity and short-term memory through a non-inflammatory IL-17-dependent mechanism.

2019-10-16 | PXD007574 | Pride

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

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2023-07-20 | PXD039463 | Pride

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