Distinct subpopulations of DN1 thymocytes exhibit preferential γδ T lineage potential

Oh, Seungyoul; Tomei, Sara; Liu, Xin; Naik, Shalin H.; Gray, Daniel H.D.; Chong, Mark M.W.

doi:10.1101/2022.02.25.481936

Cited by 2 publications

(10 citation statements)

References 69 publications

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“…CD117 high versus CD117 low delineated DN2a versus DN2b cells as defined by the Rothenberg laboratory 5 and we recently showed that simultaneous inclusion of CD90 achieves better resolution. 3 Consistent with the scRNA-seq analysis (Figure 2), all DN1 subpopulations exhibited minimal cell cycling, with only about 5% of cells in S or G2/M phases (Figure 3). Also consistent with the scRNA-seq analysis, there was then a clear upregulation in cycling cells at DN2a, with one-quarter of cells in S or G2/M phases.…”

Section: Facs Analysis Confirms That Proliferation Is Upregulated At ...supporting

confidence: 79%

“…We recently published three 109 scRNA-seq data sets of DN thymocytes. 3 The first consisted of total DN and TCRcd + thymocytes, the second data set consisted only of DN1 and DN2 thymocytes and the third data set was generated from DN1/DN2, DN3 and TCRcd + thymocytes sorted separately and then mixed back together after sorting (Figure 1 and Supplementary figure 2). These sort strategies were employed to ensure that enough DN1 and DN2 thymocytes could be captured.…”

Section: Resultsmentioning

confidence: 99%

“…One corresponding to the ab developmental pathway, ending with DN4 cells; one corresponding to the cd pathway, developing directly from DN1 cells; and one terminating with DN3 cells that had failed b-selection, which express genes associated with apoptosis and cellular senescence. 3…”

Section: Resultsmentioning

confidence: 99%

“…However, cd T cells develop from the DN1 and DN2 stages. 3,4 Two key developmental checkpoints occur during the DN stages. The first is T lineage commitment at DN2, when multipotency is lost and differentiation into a T-cell is irreversibly fixed.…”

Section: Introductionmentioning

confidence: 99%

“…Most mature T‐cell lineages are selected from double positive–staged thymocytes. However, γδ T cells develop from the DN1 and DN2 stages 3,4 …”

Section: Introductionmentioning

confidence: 99%

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Mapping the two distinct proliferative bursts early in T‐cell development

Parikh

Xiao

et al. 2023

Immunol Cell Biol

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T‐cell development occurs in the thymus and is tightly regulated to produce a diverse enough repertoire of mature T cells that can recognize any potential pathogen. The development of T cells is dependent on small numbers of uncommitted precursors that continually seed the thymus from the bone marrow. As they progress along the developmental pathway, there is a massive expansion in cell number to generate the necessary diversity in T‐cell receptor chain usage. It is recognized that there are two proliferative bursts that occur early in T‐cell development, one prior to β‐selection and one after, and these are responsible for the expansion. While the proliferation following β‐selection is well‐characterized, the earlier proliferative burst has yet to be precisely defined. In this study, we employ single‐cell RNA sequencing coupled to trajectory inference methods to pinpoint when in T‐cell development thymocytes are induced into cell cycle. We show that the first proliferative burst is initiated in the double‐negative (DN) 2a stage before T lineage commitment occurs, with cell cycling downregulated by the DN3a stage. A second burst is then initiated at the DN3b stage, immediately after β‐selection. We subsequently employ fluorescence‐activated cell sorting–based analysis for DNA content to confirm these two proliferative bursts.

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Section: Facs Analysis Confirms That Proliferation Is Upregulated At ...supporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Most mature T‐cell lineages are selected from double positive–staged thymocytes. However, γδ T cells develop from the DN1 and DN2 stages 3,4 …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mapping the two distinct proliferative bursts early in T‐cell development

Parikh

Xiao

et al. 2023

Immunol Cell Biol

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SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

Mistri,

Hilton,

Horrigan

et al. 2024

Preprint

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During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we utilized a single-cell proteogenomics approach coupled with γδ V(D)J profiling to map the transcriptional landscape, TCR repertoire, and developmental checkpoints of SAP-dependent mouse γδ T cells. We found that SAP mediates its effects on immature, uncommitted thymic γδ T cells and that it simultaneously promotes progression through the γδT17 developmental pathway while also inhibiting the diversion of γδ T cells into the αβ T cell pathway. The redirection of γδ T cell clonotypes into the αβ T cell pathway was associated with a decreased frequency of these mature clonotypes in neonatal thymus, and an altered γδT17 TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent γδT1 Vγ4 T cell subset. Altogether, these data suggest that SLAM/SAP signaling acts during the very early stages of γδ T cell development, where it regulates critical pathways involved in the development of specific γδ T effector subsets, and influences the establishment of a unique innate-like γδ TCR repertoire in both the thymus and the periphery.

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Distinct subpopulations of DN1 thymocytes exhibit preferential γδ T lineage potential

Cited by 2 publications

References 69 publications

Mapping the two distinct proliferative bursts early in T‐cell development

Mapping the two distinct proliferative bursts early in T‐cell development

SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

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