Ontogenic timing, T cell receptor signal strength, and Notch signaling direct γδ T cell functional differentiation in vivo

Abstract

SUMMARY γδ T cells form an integral arm of the immune system and are critical during protective and destructive immunity. However, how γδ T cells are functionally programmed in vivo remains unclear. Here, we employ RBPJ-inducible and KN6-transgenic mice to assess the roles of ontogenic timing, T cell receptor (TCR) signal strength, and Notch signaling. We find skewing of Vγ1 + cells toward the PLZF + Lin28b + lineage at the fetal stage. Generation of interleukin-17 (IL-17)-producing γδ T cells is favored during, although not exclusive to, the fetal stage. Surprisingly, Notch signaling is dispensable for peripheral γδ T cell IL-17 production. Strong TCR signals, together with Notch, promote IL-4 differentiation. Conversely, less strong TCR signals promote Notch-independent IL-17 differentiation. Single-cell transcriptomic analysis reveals differential programming instilled by TCR signal strength and Notch for specific subsets. Thus, our results precisely define the roles of ontogenic timing, TCR signal strength, and Notch signaling in γδ T cell functional programming in vivo .

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

“…6,34 The absence ofγ δ T cells in the Indu- Rag1 skin was confirmed ( Fig 4B ) 6 . Moreover, in line with a previous report, 32 lung Vγ1 and Vγ4 cells believed to solely develop from adult thymus precursors were generated in such mice ( Suppl. Fig 5A-B ).…”

“…Notch is known to be one of the key factors for γδ17 cell fate decisions in the perinatal period. 19,32 Alternatively, they might be derived from different precursors or/and may proceed via different developmental pathways compared to perinatal cells. 18 To our surprise, only very few differentially accessible gene regions were identified within WT and Indu-Rag1 γδ17 cell Clusters.…”

“…6,11 In contrast, few studies suggest that IL-17 production can be induced also from postnatal thymus-derived Vγ4 cells under certain circumstances. 20,21,32 Thus, it remains controversial whether Vγ4 + γ δ 17 cells derive from the pre-as well as the postnatal thymus. Therefore, we intended to re-investigate transcriptional programs of developing Vγ4 cells in adult thymus.…”

Bibliometric analysis of single-cell sequencing researches on immune cells and their application of DNA damage repair in cancer immunotherapy

“…( 46 ) to predict tumor response to immunotherapy and provide reference for clinical decision making. Furthermore, Chenet al ( 47 ) accurately defined the time of ontogeny and the direction of functional differentiation by detecting γδ TCR through single-cell sequencing. Studies have shown that γδ T cells can exist in immunogenic mismatch repair-deficient colorectal cancer ( 48 ), and can be used as a tool to predict the response to immunotherapy ( 49 ), providing new insights for future research.…”

Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation

“…This paradigm also applies to committed γδ T cells that progress along the IFNγ-producing γδT1 fate or the γδT17 fate ( 45 ) ( Figure 1B ). Engagement of strong γδ TCR ligands in conjunction with co-stimulatory molecules results in strong TCR signaling and the γδT1 developmental outcome, whereas a less strong TCR signal leads to the γδT17 fate ( 46 – 48 ). All these lineage choices are intimately associated with the balance between Id3 and E proteins ( 49 , 50 ).…”