New insights into TCR β-selection

TCR β-selection is a crucial checkpoint for normal mammalian T cell development. Malfunction of this process can lead to a developmental block and/or predisposition to oncogenic transformation. β-selection enforces αβ lineage commitment. Pre-TCR signals can be triggered autonomously or can be ligand initiated, contributing to TCRβ diversity during β-selection. Coordinated Notch and pre-TCR signaling can result in an optimal proliferative response through the degradation of the cyclin-dependent kinase inhibitor, Cdkn1b, in mice. Distinctive elements of the β-selection process in mice and humans underscore the need for continued research to understand human T cell ontogeny. T cell receptor (TCR) β-selection (herein referred to as β-selection) is a pivotal checkpoint in mammalian T cell development when immature CD4–CD8– T-cells (thymocytes) express pre-TCR following successful Tcrb gene rearrangement. At this stage, αβ T cell lineage commitment and allelic exclusion to restrict one β-chain per cell take place and thymocytes undergo a proliferative burst. β-selection is known to be crucially dependent upon synchronized Notch and pre-TCR signaling; however, other necessary inputs have been identified over the past decade, expanding our knowledge and understanding of the β-selection process. In this review, we discuss recent mechanistic findings that have enabled a more detailed decoding of the molecular dynamics of the β-selection checkpoint and have helped to elucidate its role in early T cell development. T cell receptor (TCR) β-selection (herein referred to as β-selection) is a pivotal checkpoint in mammalian T cell development when immature CD4–CD8– T-cells (thymocytes) express pre-TCR following successful Tcrb gene rearrangement. At this stage, αβ T cell lineage commitment and allelic exclusion to restrict one β-chain per cell take place and thymocytes undergo a proliferative burst. β-selection is known to be crucially dependent upon synchronized Notch and pre-TCR signaling; however, other necessary inputs have been identified over the past decade, expanding our knowledge and understanding of the β-selection process. In this review, we discuss recent mechanistic findings that have enabled a more detailed decoding of the molecular dynamics of the β-selection checkpoint and have helped to elucidate its role in early T cell development. process by which only one allele of a TCR gene (α, β, γ, or δ) is expressed while expression of the other allele is suppressed. enzyme inhibitor encoded by Cdkn1b in mice; belongs to the Cip/Kip family of Cdk inhibitor proteins, which regulate cell cycle progression. CD4−CD8− thymocytes; the most immature stage of thymocyte development. CD4+CD8+ thymocytes; intermediate stage of thymocyte development. Positive selection occurs at the DP stage. most-immature subpopulation of DP thymocytes recently generated from ISP thymocytes and transiently continue to proliferate. the most immature hematopoietic progenitor cells; can develop into all blood cell lineages, including white blood cells (lymphocytes and granulocytes), myeloid cells, red blood cells, and platelets; primarily found in the fetal liver and the adult bone marrow. CD4–CD8+ stage of T cell development; a transition stage from Notch-dependent survival and proliferation to Notch-independent survival and proliferation. Distinguished from mature CD8 SP by the absence of αβ-TCR surface expression. interface between an antigen-presenting cell or target cell and a lymphocyte, such as a T/B cell or natural killer cell. new theory for β-selection postulating that pre-TCRs bind to potential ligands (e.g., self-pMHC) to drive pre-TCR signaling. The alternative is autonomous or ligand- independent pre-TCR signaling. small single-stranded non-coding RNA molecules that base-pair with complementary sequences within mRNA molecules and result in RNA silencing and post-transcriptional regulation of gene expression. a spectroscopic technique to observe local magnetic fields around atomic nuclei. instrument that uses highly focused laser beams to hold and manipulate microscopically small objects, such as biological molecules or even living cells. occurs at the DP stage; ensures that T cells have successfully rearranged their Tcra locus, express surface TCRs, and can recognize self-peptide–MHC complexes with appropriate affinity. invariant component of the pre-TCR complex encoded by the pTa gene. complex that regulates β-selection; comprises a heterodimer of the TCRβ subunit generated by V-D-J recombination in association with the invariant pre-TCRα (pTα) chain and the invariant CD3 signal transducing subunits. nuclear hormone receptor promoting thymocyte differentiation into proinflammatory T helper 17 (Th17) cells. CD4+CD8−; CD4 SP or CD4−CD8+; CD8 SP thymocytes; final stage of thymocyte development. Mature CD4 SP and CD8 SP thymocytes exit the thymus and populate peripheral lymphoid organs. Negative selection occurs primarily at the late DP and immature SP stages. aggressive malignant neoplasm of transformed thymocytes or T cells. essential for Tcra locus germline transcription and primary Vα-to-Jα recombination during thymocyte development. promote Tcrd and Tcrg locus germline transcription and contribute to V-D-J recombination. specialized primary lymphoid organ of the immune system, in which T cells mature. The thymus stroma is composed primarily of cortical and medullary epithelial cells as well as bone marrow-derived hematopoietic cells, including dendritic cells and macrophages that release factors and provide interactions required for T cell development. process of somatic recombination by which T cells and B cells semi-randomly assemble different gene segments [known as variable (V), diversity (D), and joining (J) genes] to generate the highly diverse repertoire of antibodies (immunoglobulins) and TCRs expressed by B cells and T cells, respectively. recombination by which TCRα genes undergo DNA rearrangement to assemble different gene segments [e.g. variable (V) and joining (J) genes].