Interaction between γδTCR signaling and the E protein‐Id axis in γδ T cell development

Abstract

Lymphocytes with innate-like qualities such as γδ T cells, invariant natural killer T cells (iNKT cells), and innate lymphoid cells (ILCs) serve unique and critical roles within the immune system. γδ T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and serve as an important early source of interleukin (IL)-17 under inflammatory conditions. 1,2 γδ T cell subsets share effector programs with CD4 (helper) and CD8 (cytotoxic) T cells, but acquire their functional abilities by different developmental routes. Most γδ T cells differentiate into subsets with distinct effector functions in the thymus and can be rapidly activated in the periphery. To understand how divergent developmental pathways can lead to the same functional outcome, it is necessary to define the gene regulatory networks that operate in peripheral αβ T cells versus those that drive γδ T cell differentiation in the thymus. Our studies focus on the E protein transcription factor HEB, and the transcriptional regulatory network governed by HEB function. We have shown that the absence of HEB factors inhibits the development of IL-17 expressing γδ T cells (γδT17 cells), while allowing the development of interferon (IFN)γ-producing γδ T cells (γδT1 cells). 3 HEB is upstream of the known cascade of transcriptional regulatory events that drive γδT17 development, including Sox13, Sox4, and RORγt, placing it at the top of the hierarchy that controls this lineage choice. In this review, we will expand upon these results and place them in

Identification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis

“…The type 3 and type 2 developmental pathways were largely shared but split at the final maturation stage. Overall, based on the expression patterns of TCR-signaling related markers 57 , 96 , 134 , 140 and of the transcription factor PLZF 103 , 110 , 134 , 141 , 142 , we propose that differences in timing and strength in TCR signaling result in associated differences of the transcription factor PLZF that then guides the final thymic γδ effector fate.…”

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

“…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 ).…”

Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

“…However, γδTCR‐restricted backgrounds and in vitro culture models showed that loss of Id3 activity predisposes DN3 cells to enter the αβ T cell lineage even when a γδTCR signal is received, revealing the role of Id3 in the αβ/γδ lineage choice (Lauritsen et al, 2009). While periods of TCR signaling followed by transient periods of Id3 expression are essential for T cell development, it is unclear how the balance between E protein and Id3 activity controls E protein target gene expression (Anderson & Selvaratnam, 2020).…”

“…αβ T cells express a TCR composed of TCRα and TCRβ chains and include the conventional “helper” and “killer” T cells that execute the adaptive immune response. γδ T cells express a complex of TCRγ and TCRδ chains which are tightly linked to their functional capabilities (Anderson & Selvaratnam, 2020). γδ T cells perform critical functions, including defense against infection, cancer cell lysis, and maintenance of microbial homeostasis and barrier tissue integrity (Chen et al, 2020; Hovav et al, 2020; Mikulak et al, 2019; Papotto et al, 2021).…”

“…As with αβ T cells, there are four main categories of responses available to γδ T cells, including a cytotoxic program and three different cytokine profiles: the Th1 program (IFNγ) and Th2 program (IL‐4), and a Th17 program (IL‐17). These properties are selectively imparted to successive waves of γδ T cells during specific stages of fetal and adult life (Anderson & Selvaratnam, 2020). Vγ5+ Vδ1+ γδ T cells comprise the first γδ T subset to arise in the fetal thymus (Havran & Allison, 1988).…”