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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)

2023-03-01 | GSE225034 | GEO

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

2023-03-01 | GSE225032 | GEO

Haplo / Allogeneic NKG2DL-targeting Chimeric Antigen Receptor-grafted γδ T Cells for Relapsed or Refractory Solid Tumour

Project description:This clinical trial is an open-label, single-centre, dose escalation, phase I study designed to investigate the safety and tolerability of Haploidentical / Allogeneic NKG2DL-targeting Chimeric Antigen Receptor-grafted Gamma Delta (γδ) T Cells (CTM-N2D) in Subjects with Relapsed or Refractory Solid Tumour. The study objectives of this phase I study are to determine the safety, activity and the safe dose of haploidentical or allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells given four times weekly in patients with relapsed or refractory solid tumors of different types.

| 2317628 | ecrin-mdr-crc

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.

2023-12-25 | GSE251670 | GEO

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

Project description:TCR γ chain loci of mice have seven variable (Vγ) gene segments (Vγ1, Vγ2, Vγ3, Vγ4, Vγ5, Vγ6, and Vγ7) using the Heilig and Tonegawa nomenclature. Vγ6+ γδ T cells, which develop in the thymus at the perinatal stage, are distributed within the mucosal tissues in the periphery. Vγ6+ γδ T cells are exclusive interleukin (IL)-17 producers among γδ T cells, and Vγ6+ IL-17A+ γδ T (γδT17) cells play important roles in protection against microbial infection and in the pathogenesis of inflammatory diseases, such as colitis and autoimmune diseases. We have previously reported that γδT17 cells develop from the CD4–CD8– (DN)2b stage in the thymus at the prenatal stage in a Bcl11b-dependent manner. However, details of the development of Vγ6+ γδT17 cells remain obscure. To analyze Vγ6+ γδ T cells in detail, we recently developed a monoclonal antibody (mAb; termed 1C10-1F7) specific to mouse Vg6 chain. Use of this mAb revealed that Vγ6+ γδ T cells in 0-day-old thymus were co-localized with medullary thymic epithelial cells (mTECs), which regulate T cell tolerance by self-antigen presentation using major histocompatibility complex (MHC) class II. Here, we report that MHC class II in the thymus inhibits the generation of Vγ6+ γδT17 cells.

2022-08-01 | GSE180320 | GEO

CD117, CD200 and CD371 identifies seven populations of γδ thymocytes programmed towards three distinct effector subsets in adult mice

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

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Project description:Checkpoint inhibition (CPI), particularly that targeting the inhibitory co-receptor, programmed cell death protein (PD-1), has transformed cancer care. Although CPI can de repress cancer antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings γδ T cells have been implicated, but the immunological significance of PD-1 expression by tissue associated human Vδ1+ cells remains uncharacterised. Here we demonstrate that a transcriptional signature of intratumoral Vδ1+ cells predicts response to anti-PD-1 in patients with melanomas of relatively low neoantigen load. Moreover, by employing a protocol yielding substantial numbers of human skin γδ cells, we show that PD-1+ Vδ1+ cells display a transcriptomic programme of tissue-residence, survival/self-renewal, and functional competence distinct from the canonical exhaustion programme of co-located PD- 1+ CD8+ αβ T cells. Indeed, skin PD-1+ Vδ1+ cells retained effector responses to T cell receptor signalling that were inhibitable by PD-1 engagement and partially derepressed by CPI. The biological and therapeutic implications are both discussed.

2023-09-25 | GSE232529 | GEO

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

Project description:Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD 1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

2023-07-20 | PXD039463 | Pride

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