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Single-cell transcriptomics uncovers an instructive T-cell receptor role in adult γδ T-cell lineage commitment

ABSTRACT: After entering the adult thymus, bipotent T-cell progenitors give rise to αβ- or γδ-T-cells. To determine whether the γδ T-cell receptor (TCR) has an instructive role in γδ-T-cell lineage commitment or only 'confirms' a pre-established γδ-Τ cell lineage state, we exploited mice lacking expression of LAT, an adaptor required for γδ TCR signaling. Although these mice showed a T-cell development block at the CD4-CD8- double-negative (DN) 3 stage, 0.3% of their DN3 cells expressed intermediate levels of γδ-TCR (further referred to as γδint) at their surface. Single-cell transcriptomics of LAT-deficient DN3 γδint cells demonstrated no sign of commitment to the γδ-T cell lineage, apart from γδ-TCR expression. Although the lack of LAT is thought to tightly block DN3 cell development, we unexpectedly found that 25% of LAT-deficient DN3 γδint cells were actively proliferating and progressed up to the DN4 stage. However, even those cells failed to turn on the transcriptional program associated with the γδ-T-cell lineage. Therefore, the γδ-TCR-LAT signaling axis builds upon a γδ-T-cell uncommitted lineage state to fully instruct adult γδ-T-cell lineage specification.

SUBMITTER: Dr. Bernard Malissen

PROVIDER: S-SCDT-EMBOJ-2021-110023 | biostudies-other |

REPOSITORIES: biostudies-other

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Single-cell transcriptomics uncovers an instructive T-cell receptor role in adult γδ T-cell lineage commitment.

Project description:After entering the adult thymus, bipotent T-cell progenitors give rise to αβ or γδ T cells. To determine whether the γδ T-cell receptor (TCR) has an instructive role in γδ T-cell lineage commitment or only "confirms" a pre-established γδ Τ-cell lineage state, we exploited mice lacking expression of LAT, an adaptor required for γδ TCR signaling. Although these mice showed a T-cell development block at the CD4- CD8- double-negative third (DN3) stage, 0.3% of their DN3 cells expressed intermediate levels of γδ TCR (further referred to as γδint ) at their surface. Single-cell transcriptomics of LAT-deficient DN3 γδint cells demonstrated no sign of commitment to the γδ T-cell lineage, apart from γδ TCR expression. Although the lack of LAT is thought to tightly block DN3 cell development, we unexpectedly found that 25% of LAT-deficient DN3 γδint cells were actively proliferating and progressed up to the DN4 stage. However, even those cells failed to turn on the transcriptional program associated with the γδ T-cell lineage. Therefore, the γδ TCR-LAT signaling axis builds upon a γδ T-cell uncommitted lineage state to fully instruct adult γδ T-cell lineage specification.

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Project description:In the thymus, hematopoietic progenitors commit to the T cell lineage and undergo sequential differentiation to generate diverse T cell subsets, including major histocompatibility complex (MHC)-restricted αβ T cell receptor (TCR) T cells and non-MHC-restricted γδ TCR T cells. The factors controlling precursor commitment and their subsequent maturation and specification into αβ TCR versus γδ TCR T cells remain unclear. Here, we show that the tyrosine phosphatase PTPN2 attenuates STAT5 (signal transducer and activator of transcription 5) signaling to regulate T cell lineage commitment and SRC family kinase LCK and STAT5 signaling to regulate αβ TCR versus γδ TCR T cell development. Our findings identify PTPN2 as an important regulator of critical checkpoints that dictate the commitment of multipotent precursors to the T cell lineage and their subsequent maturation into αβ TCR or γδ TCR T cells.

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T cell receptor-instructed alphabeta versus gammadelta lineage commitment revealed by single-cell analysis.

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Single-cell transcriptomics of adult gd T-cell lineage commitment highlights its TCR-instructive nature

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-01 | GSE184545 | GEO

Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics.

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Single-cell transcriptomics of adult gd T-cell lineage commitment highlights its TCR-instructive nature II

Project description:Single cell RNA-seq study of T lymphocyte differentiation WT and LAT deficient mice in order to deciphy gd T-cell lineage commitment.

2022-01-01 | GSE184544 | GEO

Single-cell transcriptomics of adult gd T-cell lineage commitment highlights its TCR-instructive nature I

Project description:Single cell RNA-seq study of T lymphocyte differentiation WT and LAT deficient mice in order to deciphy gd T-cell lineage commitment.

2022-01-01 | GSE184483 | GEO

A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis.

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