The E protein-TCF1 axis controls γδ T cell development and effector fate

E-protein transcription factors limit group 2 innate lymphoid cell (ILC2) development while promoting T cell differentiation from common lymphoid progenitors. Inhibitors of DNA binding (ID) proteins block E-protein DNA binding in common lymphoid progenitors to allow ILC2 development. However, whether E-proteins influence ILC2 function upon maturity and activation remains unclear. Mice that overexpress ID1 under control of the thymus-restricted proximal Lck promoter (ID1 tg/WT ) have a large pool of primarily thymus-derived ILC2s in the periphery that develop in the absence of E-protein activity. We used these mice to investigate how the absence of E-protein activity affects ILC2 function and the genomic landscape in response to house dust mite (HDM) allergens. ID1 tg/WT mice had increased KLRG1 2 ILC2s in the lung compared with wild-type (WT; ID1 WT/WT ) mice in response to HDM, but ID1 tg/WT ILC2s had an impaired capacity to produce type 2 cytokines. Analysis of WT ILC2 accessible chromatin suggested that AP-1 and C/EBP transcription factors but not E-proteins were associated with ILC2 inflammatory gene programs. Instead, E-protein binding sites were enriched at functional genes in ILC2s during development that were later dynamically regulated in allergic lung inflammation, including genes that control ILC2 response to cytokines and interactions with T cells. Finally, ILC2s from ID1 tg/WT compared with WT mice had fewer regions of open chromatin near functional genes that were enriched for AP-1 factor binding sites following HDM treatment. These data show that E-proteins shape the chromatin landscape during ILC2 development to dictate the functional capacity of mature ILC2s during allergic inflammation in the lung.

Section: Discussionmentioning

confidence: 57%

E-Protein Inhibition in ILC2 Development Shapes the Function of Mature ILC2s during Allergic Airway Inflammation

Barshad

Webb

Ting

et al. 2022

“…It is rapidly induced by Notch signaling in thymic settling progenitors (9597), is necessary and sufficient to initiate T cell specification (95), and imprints the epigenetic landscape used by all mature T cells (98). TCF-1 (and LEF-1) is proposed to broadly regulate T cell function, including the acquisition of effector functions in mainstream and preset ab T cells (99), as well as in gd T cells (100). Interestingly, a TCF-1 ortholog is expressed in lamprey VLRA 1 lymphocytes (3), suggesting that its functions are evolutionarily conserved.…”

Section: Transcription Factors Underlying Innate-like T Cell Developmentmentioning

confidence: 99%

γδ T, NKT, and MAIT Cells During Evolution: Redundancy or Specialized Functions?

Harly

Robert

Legoux

et al. 2022

Self Cite

Innate-like T cells display characteristics of both innate lymphoid cells (ILCs) and mainstream αβ T cells, leading to overlapping functions of innate-like T cells with both subsets. In this review, we show that although innate-like T cells are probably present in all vertebrates, their main characteristics are much better known in amphibians and mammals. Innate-like T cells encompass both γδ and αβ T cells. In mammals, γδ TCRs likely coevolved with molecules of the butyrophilin family they interact with, whereas the semi-invariant TCRs of iNKT and mucosal-associated invariant T cells are evolutionarily locked with their restricting MH1b molecules, CD1d and MR1, respectively. The strong conservation of the Ag recognition systems of innate-like T cell subsets despite similar effector potentialities supports that each one fulfills nonredundant roles related to their Ag specificity.

“…However, ID2 mediates these different functions through distinct mechanisms, with effector maturation being dependent on ID2's ability to dampen E protein function at an intronic enhancer for Tcf7 (encoding TCF1), and expansion being dependent on repression of the suppressor of cytokine signaling gene Socs3 (123, 124). Whether ID2 and ID3 limit Tcf7 transcription early in iNKT cell development remains to be determined, but they do play a similar role in gd T cells (125). Of note, TCF1 and LEF1 are both required for early iNKT cell expansion and iNKT2 differentiation, and thus overexpression of TCF1 or LEF1, which is also regulated by E proteins, might derail the iNKT1 cell program (13,14).…”

Section: The E Proteinid Protein Axismentioning

confidence: 99%

Genomic and Transcriptional Mechanisms Governing Innate-like T Lymphocyte Development

Morgan

Kee

2022

Innate-like lymphocytes are a subset of lymphoid cells that function as a first line of defense against microbial infection. These cells are activated by proinflammatory cytokines or broadly expressed receptors and are able to rapidly perform their effector functions owing to a uniquely primed chromatin state that is acquired as a part of their developmental program. These cells function in many organs to protect against disease, but they release cytokines and cytotoxic mediators that can also lead to severe tissue pathologies. Therefore, harnessing the capabilities of these cells for therapeutic interventions will require a deep understanding of how these cells develop and regulate their effector functions. In this review we discuss recent advances in the identification of the transcription factors and the genomic regions that guide the development and function of invariant NKT cells and we highlight related mechanisms in other innate-like lymphocytes.