Transcription factors and target genes of pre-TCR signaling

Abstract

Almost 30 years ago pioneering work by the laboratories of Harald von Boehmer and Susumo Tonegawa provided the first indications that developing thymocytes could assemble a functional TCRβ chain-containing receptor complex, the pre-TCR, before TCRα expression. The discovery and study of the pre-TCR complex revealed paradigms of signaling pathways in control of cell survival and proliferation, and culminated in the recognition of the multifunctional nature of this receptor. As a receptor integrated in a dynamic developmental process, the pre-TCR must be viewed not only in the light of the biological outcomes it promotes, but also in context with those molecular processes that drive its expression in thymocytes. This review article focuses on transcription factors and target genes activated by the pre-TCR to drive its different outcomes. KeywordsThymocyte development Pre-TCR expression Pre-TCR signaling Transcription factor Gene expression NF-κB NFATc NFAT5 ETS1 E2A/HEB proteins Bcl2A1 p53 Intrinsic apoptotic pathway We apologize to those authors whose work was not cited due to space limitations or our oversight. The thymus as the place for T cell development: short overview of thymocyte developmentThe thymus is the organ that supports the differentiation and selection of T cells. The thymic stroma promotes T cell development by producing growth factors and ligands for receptors expressed in thymocytes. During mouse embryogenesis, the thymic rudiment differentiates into the cortical and medullary thymic epithelial cell subsets (cTECs and mTECs), the major constituents of thymic stroma [ 1 ]. Only a small subset of hematopoietic precursors with T-lineage potential is able to enter the thymus [ 2 -4 ]. Early lymphoid progenitors (ELPs) enter the thymus at the cortico-medullary junction [ 5 ] and begin their development into T cells through several phenotypically distinct and sequential stages, known as double-negative (DN), double-positive (DP) and singlepositive (SP) based on the surface expression of the co-receptors CD4 and CD8. DN cells are further divided into four consecutive stages on the basis of CD44 and CD25 expression: DN1 (CD44 CD25 ), DN2 (CD44 CD25 ), DN3 (CD44 CD25 ) and DN4 (CD44 CD25 ) cells [ 6 ].Initial thymocyte development from DN1 to DN3 is promoted by molecules produced by cTECs, mainly interleukin-7 (IL-7) and Notch ligands [ 7 , 8 ]. ELPs that home into the thymus retain the expression of the surface receptor c-kit [ 9 ], indeed a small subset of early thymocyte progenitors (EPs) defined within DN1 prothymocytes still has high expression of c-kit [ 10 ]. DN thymocytes move to the subcapsular region of the thymic cortex and express the pre-T-cell receptor (pre-TCR) complex [ 11 , 12 ]. The pre-TCR is a unique molecular complex with an invariant pre-TCRα (pTα) chain associated with a recombined TCRβ chain and the signaling 1,3,* molecules CD3γ, CD3δ, CD3ε and CD3ζ, which also form part of the mature TCR [ 12 , 13 ]. The pre-TCR, along with the DeltaNotch interaction [ 14 ], initiates t...

Shorter TCR β-Chains Are Highly Enriched During Thymic Selection and Antigen-Driven Selection

“…In the case of developing T cells, the assembly of in-frame receptor genes is low frequency event. Positively selected CD4 + CD8 + double-positive thymocytes then start relocating to the medulla and differentiate into T-helper CD4 + single positive (SP) thymocytes that have the ability to recognize peptides presented by MHC class II molecules, or T-cytotoxic CD8 + SP thymocytes that can interact with MHC class I molecules (8). Subsequently, T cells with excessive self reactivity are deleted in the thymus, a process called negative selection (9).…”

Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition

“…In DMSO treated cells, Notch was concentrated at the MTOC, but, similar to LAT, was much more diffuse following How might such a disruption in the immunological synapse and TCR signalling alter progression from DN3b Pre to DN3b Post ? A collaboration between pre-TCR and Wnt signalling is well established, with two core Wnt pathway transcriptional regulators: β-catenin and Lef1/TCF-1 essential to βselection (Gounari et al, 2001;López-Rodríguez et al, 2015;Staal and Clevers, 2005;Travis et al, 1991;Xu et al, 2009;Zhao et al, 2021). TCF-1 and Lef1 can directly modify histone acetylation, and this function is inhibited by the pharmacological HDAC inhibitors, Tubacin and Vorinostat, (Xing et al, 2016;Zhao et al, 2021).…”

Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance

“…TECs located in the medulla (mTECs) also express autoimmune regulator ( AIRE ), a transcription factor that induces expression of tissue‐restricted self‐antigens . TCR beta and gamma chain VDJ rearrangements occur simultaneously in developing T cells, and lineage commitment occurs following successful chain rearrangement and signaling through a pre‐TCR . Beta lineage‐committed thymocytes then undergo alpha chain VJ rearrangement.…”