New insights into TCR β-selection

Dutta, Avik; Zhao, Binghao; Love, Paul E.

doi:10.1016/j.it.2021.06.005

Cited by 55 publications

(50 citation statements)

References 131 publications

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“…The outcome of these TCR rearrangement events is the main driver of the developmental bifurcation of the αβand γδ-lineages which mainly occurs at the ISP stage, and this allows both lineages to mature into distinct T cell subsets that have unique functions in the periphery [29]. During αβ-lineage development, an in-frame rearranged TCRβ chain associates with the invariant pre-T cell receptor α chain ( pTα) in order to generate the pre-TCR that induces β-selection, an event that mainly occurs at the CD4 + immature single positive (ISP) stage [30][31][32][33]. Upon pre-TCR signaling, developing thymocytes receive proliferation and survival signals and up-regulate CD8β to differentiate into CD4 + CD8β + double positive (DP) T cells [34].…”

Section: Human T Cell Development In Vivomentioning

confidence: 99%

Modeling of human T cell developmentin vitroas a read-out for hematopoietic stem cell multipotency

Strubbe

Taghon

2021

Biochemical Society Transactions

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Hematopoietic stem cells (HSCs) reside in distinct sites throughout fetal and adult life and give rise to all cells of the hematopoietic system. Because of their multipotency, HSCs are capable of curing a wide variety of blood disorders through hematopoietic stem cell transplantation (HSCT). However, due to HSC heterogeneity, site-specific ontogeny and current limitations in generating and expanding HSCs in vitro, their broad use in clinical practice remains challenging. To assess HSC multipotency, evaluation of their capacity to generate T lymphocytes has been regarded as a valid read-out. Several in vitro models of T cell development have been established which are able to induce T-lineage differentiation from different hematopoietic precursors, although with variable efficiency. Here, we review the potential of human HSCs from various sources to generate T-lineage cells using these different models in order to address the use of both HSCs and T cell precursors in the clinic.

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Section: Human T Cell Development In Vivomentioning

confidence: 99%

Modeling of human T cell developmentin vitroas a read-out for hematopoietic stem cell multipotency

Strubbe

Taghon

2021

Biochemical Society Transactions

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“…The preTCR includes a fully rearranged β-chain that pairs with an invariant preTα chain and is expressed on a subset of DN thymocytes known as DN3. Signaling from the preTCR drives the differentiation (β selection) of DN3 thymocytes to DN4 and subsequently to the DP stage [2,3]. At the DP stage, thymocytes express fully rearranged TCRα and TCRβ chains, resulting in the expression of a mature TCR.…”

Section: Introductionmentioning

confidence: 99%

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

Kästle

Merten

Hartig

et al. 2022

IJMS

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Signaling via the TCR, which is initiated by the Src-family tyrosine kinase Lck, is crucial for the determination of cell fates in the thymus. Because of its pivotal role, ablation of Lck results in a profound block of T-cell development. Here, we show that, in addition to its well-known function in the initiation of TCR signaling, Lck also acts at a more downstream level. This novel function of Lck is determined by the tyrosine residue (Y192) located in its SH2 domain. Thymocytes from knock-in mice expressing a phosphomimetic Y192E mutant of Lck initiate TCR signaling upon CD3 cross-linking up to the level of PLC-γ1 phosphorylation. However, the activation of downstream pathways including Ca2+ influx and phosphorylation of Erk1/2 are impaired. Accordingly, positive and negative selections are blocked in LckY192E knock-in mice. Collectively, our data indicate that Lck has a novel function downstream of PLCγ-1 in the regulation of thymocyte differentiation and selection.

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“…Mature T cells originate in the thymus and after going through various developmental stages they exit the thymus to circulate in the peripheral lymphoid organs including the spleen and lymph nodes [ 1 , 2 ]. Originating in the bone marrow or fetal liver, thymic seeding progenitor cells (TSPs) (also known as early thymic progenitor cells (ETPs) or DN1 cells (CD4 − CD8 − double negative; DN)) enter the thymus, where they progress through four DN stages (DN1-4) ( Figure 1 ) [ 3 ]. DN3 cells expressing the pre-TCR (pre-T cell receptor) transit to the DP (CD4 + CD8 + , double positive; DP) stage ( Figure 1 ) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Originating in the bone marrow or fetal liver, thymic seeding progenitor cells (TSPs) (also known as early thymic progenitor cells (ETPs) or DN1 cells (CD4 − CD8 − double negative; DN)) enter the thymus, where they progress through four DN stages (DN1-4) ( Figure 1 ) [ 3 ]. DN3 cells expressing the pre-TCR (pre-T cell receptor) transit to the DP (CD4 + CD8 + , double positive; DP) stage ( Figure 1 ) [ 3 , 4 ]. In the cortex, DP thymocytes undergo a process of positive and negative selection which is determined by TCR signaling in response to binding to self-peptide-self-major histocompatibility complexes (self-pMHC) and then commit to either the CD4 + or CD8 + SP (single positive; SP) lineage ( Figure 1 ) [ 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…DN3 cells expressing the pre-TCR (pre-T cell receptor) transit to the DP (CD4 + CD8 + , double positive; DP) stage ( Figure 1 ) [ 3 , 4 ]. In the cortex, DP thymocytes undergo a process of positive and negative selection which is determined by TCR signaling in response to binding to self-peptide-self-major histocompatibility complexes (self-pMHC) and then commit to either the CD4 + or CD8 + SP (single positive; SP) lineage ( Figure 1 ) [ 2 , 3 , 4 , 5 ]. Immature SP thymocytes undergo further differentiation to generate either MHC Class II restricted CD4 SP helper or MHC Class I restricted CD8 SP cytotoxic lineage cells [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

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New Insights into Epigenetic Regulation of T Cell Differentiation

Dutta

Venkataganesh

Love

2021

Cells

Self Cite

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Immature CD4− CD8− thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4+ (helper) or CD8+ (cytotoxic) T cells. Activation of naïve CD4+ and CD8+ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4+ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans.

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New insights into TCR β-selection

Cited by 55 publications

References 131 publications

Modeling of human T cell developmentin vitroas a read-out for hematopoietic stem cell multipotency

Modeling of human T cell developmentin vitroas a read-out for hematopoietic stem cell multipotency

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

New Insights into Epigenetic Regulation of T Cell Differentiation

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