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Investigating in the implications of the γδ T cell receptor in the acquisition of IL-17 producing effector functions

ABSTRACT: One common way to classify functional γδ T cell subsets is based on the expressed variable gene region of the T-cell-receptor (TCR) γ-chain. It is established that the TCRs of murine IL-17 producing γδ T cells are either Vγ6+ or Vγ4+. The majority of IL-17 producers get functionally pre-programmed in the prenatal thymus, and persist thereafter as tissue-resident cells into adulthood. Little is known about the role of the expressed TCR on IL-17 effector fate acquisition, and if also other subsets can produce IL-17 under certain circumstances. To address this question, we took advantage of a mouse model that lack the Vγ4 and Vγ6 γ-chain (Vγ4-/- / Vγ6-/- double knock-out). Initial results indicate that Vγ1+ T cells show increased IL-17 production capability in the absence of Vγ4+ and Vγ6+ γδ T cells, suggesting that the γδTCR does not always instruct the phenotype. This raises the question about the ontogenetic origin, which might be a TCR-independent default mechanism to instruct IL-17 production by γδ T cells, of IL-17+ Vγ1+ T cells. Moreover, it remains elusive if these Vγ1+ T cells (i) adopt highly similar tissue-specific gene expression programs and (ii) functionality in health and disease, than the Vγ4+ and Vγ6+ T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE284198 | GEO | 2025/09/24

REPOSITORIES: GEO

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Investigating in the implications of the γδ T cell receptor in the acquisition of IL-17 producing effector functions.

Project description:One common way to classify functional γδ T cell subsets is based on the expressed variable gene region of the T-cell-receptor (TCR) γ-chain. It is established that the TCRs of murine IL-17 producing γδ T cells are either Vγ6+ or Vγ4+. The majority of IL-17 producers get functionally pre-programmed in the prenatal thymus, and persist thereafter as tissue-resident cells into adulthood. Little is known about the role of the expressed TCR on IL-17 effector fate acquisition, and if also other subsets can produce IL-17 under certain circumstances. To address this question, we took advantage of a mouse model that lack the Vγ4 and Vγ6 γ-chain (Vγ4-/- / Vγ6-/- double knock-out). Initial results indicate that Vγ1+ T cells show increased IL-17 production capability in the absence of Vγ4+ and Vγ6+ γδ T cells, suggesting that the γδTCR does not always instruct the phenotype. This raises the question about the ontogenetic origin, which might be a TCR-independent default mechanism to instruct IL-17 production by γδ T cells, of IL-17+ Vγ1+ T cells. Moreover, it remains elusive if these Vγ1+ T cells (i) adopt highly similar tissue-specific gene expression programs and (ii) functionality in health and disease, than the Vγ4+ and Vγ6+ T cells.

2025-09-24 | GSE284167 | GEO

TCR signal strength controls thymic differentiation of discrete proinflammatory γδT cell subsetsistinct TCR signal strength requirements in the thymus

Project description:The murine thymus produces discrete γδ T cell subsets making either IFN-γ or IL-17, but the role of the TCR in this developmental process remains controversial. Here we generated a non-transgenic and polyclonal model of reduced TCR expression and signal strength selectively on γδ T cells. Mice haploinsufficient for both CD3γ and CD3δ (CD3DH) showed normal αβ thymocyte subsets but specific defects in γδ T cell development, namely impaired differentiation of IL-17-producing embryonic Vγ6+ (but not adult Vγ4+) γδ T cells and a marked depletion of IFN-γ-producing CD122+ NK1.1+ (Vγ1-biased) γδ T cells throughout life. As result, adult CD3DH mice showed defective peripheral IFN-γ responses and were resistant to experimental cerebral malaria. Thus, strong TCR signaling is required within specific developmental windows with distinct Vγ usage and differential cytokine production by effector γδ T cell subsets.

2016-03-29 | GSE71637 | 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

Vγ6+ γδ T cells play a critical role in protection against infection by Escherichia coli

Project description:γδ T cells producing interleukin 17A (IL-17A), which are mainly Vγ4 and Vγ6 subsets, are involved in protection against infection by extracellular bacteria. Using a new Vγ6-specific monoclonal antibody (mAb) (1C10-1F7) which we recently developed, we found that IL-17A+ Vγ6+ γδ T cells increased predominantly in the peritoneal cavity compared with IL-17A+ Vγ4+ γδ T cells during intraperitoneal Escherichia coli infection. The number of IL-17A+ Vγ6+ γδ T cells, which rapidly became CD69+ from CD69-, peaked at 12 h after infection. In vivo treatment with 1C10-1F7 mAb significantly inhibited the accumulation of neutrophils and hampered the resolution of E. coli infection. These results suggest that rapid activation of IL-17A+ Vγ6+ γδ T cells contributed to host defence against E. coli infection.

2020-02-28 | GSE144617 | GEO

RNA sequencing of gamma-delta T cell subsets from young and old mice

Project description:Organismal ageing is associated with loss of immune function and higher incidence of cancer. Whether the γδ T cell pool changes upon organismal ageing is not known. In this study we have characterized γδ T cells in peripheral lymph nodes from old and young mice. We found that the γδ T cell pool is severely altered in old mice. The IL-17 producing γδ lineage becomes dominating while IFN-γ producing γδ1 T cells are declining. γδTCR sequencing revealed no collapse in diversity but oligoclonal expansions in Vγ4 γδ17 subsets. Pro-tumourigenic invariant Vγ6 cells are present only in aged lymph nodes, represent the majority of γδ T cells in the tumour, and are associated with faster tumour progression.

2019-05-22 | E-MTAB-7178 | biostudies-arrayexpress

Single cell RNA sequencing of Vγ4 and Vγ6 γδT cells from different tissue

Project description:IL17-producing γδ T cells (γδ T17) mainly develop in the prenatal phase and persist as long-living self-renewing effector cell in all kind of tissues. They express polyclonal T-cell receptors (TCR), comprising public Vγ4+ and Vγ6+ TCRs with germline-like rearrangements. In particular, Vγ6+ T cells have recently been found in a variety of tissues including enthesis, gingiva or skin. However, their exchange between tissues and the mechanisms of tissue-specific adaptation and residency remain poorly understood. Here, we profiled Vγ6+ T cells isolated from thymus, peripheral lymph nodes (pLN) and skin through single-cell RNA-seq technology and compared those to Vγ4+ T cells. Our data demonstrated that Vγ6+ T cells formed highly homogenous cell populations that could be separated by tissue-specific gene expression signatures.

2018-12-07 | GSE123400 | GEO

Single-Cell RNA Sequencing of Thymic KN6 γδ T-Cells Modulated by TCR Signal Strength and Notch Signaling

Project description:γδ T-cells form an integral arm of the immune system through their rapid and potent effector functions, and are critical players during both protective and destructive immunity. However, the factors that dictate γδ T-cell functional programming in vivo remain to be fully elucidated. Here, we employed RBPJ-inducible and KN6-transgenic mice to assess the roles of ontogenic timing, T-cell receptor (TCR) signal strength, and Notch signaling in the generation of γδ T-cell functional subsets in vivo. We found skewed generation of Vγ1+ cells toward the PLZF+ γδ T-cell lineage at the fetal stage. Similarly, generation of interleukin (IL)-17 producing γδ T-cells was favored during, although not exclusive to, the fetal stage. Strong TCR signals, in conjunction with Notch, were necessary for the generation of IL-4 producing γδ T-cells. Conversely, weak TCR signals were amenable for the generation of IL-17 producing γδ T-cells, which was Notch-independent. Additionally and surprisingly, Notch signaling was also dispensable for peripheral γδ T-cell IL-17 production. Thus, our results precisely defined the roles of ontogenic timing, TCR signal strength, and Notch signaling in γδ T-cell functional programming in vivo.

2021-05-01 | GSE165908 | GEO

RNA Sequencing of Fetal and Adult Mature Thymic Vγ1+ γδ T-Cells

2021-05-01 | GSE166086 | 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

Adult thymus-derived cMaf+RORγt+γδ T cells lack Scart2 chromatin accessibility and do not reach periphery

Project description:T cell receptor (TCR) Vγ4+expressing γδT cells can be divided into IFN-γ and IL-17-producing effector T cell subsets. A bias towards γδ17 effector fate decisions is observed during early ontogeny. In contrast, the existence of Vγ4+γδ17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immatureCd24+Gzma+Vγ4 cells was found that exhibit molecular programs of γδ17 cells. These adult thymus-derived immatureCd24a+cMaf+Vγ4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore,de novogenerated γδ17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal γδT cell precursors. Together, this study provides valuable insights into developmental traits of Vγ4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of γδ17-like cells within the adult thymus.

2025-08-25 | GSE237401 | GEO

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