Chromatin Dynamics and the Development of the TCRα and TCRδ Repertoires

Carico, Zachary; Krangel, Michael S.

doi:10.1016/bs.ai.2015.07.005

Cited by 54 publications

(77 citation statements)

References 218 publications

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“…The Tcra and Tcrd genes are linked in a single genetic locus, Tcra/ Tcrd, which spans 1.8-Mb with a conserved genomic structure and a location between the olfactory receptor genes and the Dad1 gene on chromosome 14 in humans and mice [4,5,26]. The 1.7-Mb 5´-locus region includes 132 Tcra and Tcrd V (Trav and Trdv) gene segments, while the remaining 0.1-Mb 3´-locus region contains the Tcrd D and J (Trdd and Trdj) gene segments, the Tcrd constant region (Cδ), the Trdv5 gene segment, the Tcra J (Traj) gene segments, and the Tcra constant region (Cα) (Figure 2 [27,[30][31][32][33].…”

Section: Regulatory Cis-elements Present At the Tcra/tcrd Locusmentioning

confidence: 99%

“…Furthermore, two DP thymocyte populations can be distinguished based on the expression of CD71: early DP (eDP) (CD71 + ) and late DP (lDP) (CD71 -) thymocytes [3]. For αβ T-cell development, thymocytes transition from DN1 to SP thymocytes by maturing successively through the following populations: DN1, DN2, DN3a, DN3b, DN4, ISP, eDP, lDP, and SP thymocytes; whereas for γδ T-cell development, thymocytes transit only from DN1 to DN2 or DN3a before becoming mature cells [1].The loci that encode for the TCR chains are composed of dispersed variable (V), diversity (D), and joining (J) gene segments that are rearranged during thymocyte development by a process known as V(D)J recombination to generate a gene configuration capable of expressing the functional receptors, TCRαβ or TCRγδ, on the cell membrane [4,5]. The V(D)J recombination is completed in DN2 and DN3a thymocytes at the Tcrg and Tcrd loci, in DN3a thymocytes at the Tcrb locus, and in DP thymocytes at the Tcra locus [4].…”

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confidence: 99%

“…The fully contracted locus configuration in DN3a thymocytes is thought to facilitate the Tcrd VDJ recombination using the disperse Trdv gene segments across the entire locus, whereas the Tcra/Tcrd configuration in DP thymocytes is believed to facilitate the sequentially ordered primary and secondary Tcra VJ recombination (Figure 2) [5,61]. The molecular mechanism involved in the regulation of the different configurations adopted by the Tcra/Tcrd locus during thymocyte development is currently unknown.Although the 3´-end of the locus remains similarly contracted in DN3a and DP thymocytes, chromosome conformation capture experiments (3C and 4C) have distinguished two distinct functional chromatin interactions within this 0.5-Mb region of DN3a and DP thymocytes using recombinase activating gene-deficient (Rag -/-) mice (Figure 3) [5,27,28]. In Rag -/-DN3a thymocytes, a functionally relevant discrete chromatin loop mediated by CTCF-bound INT1/2 and CTCF-bound TEAp has been recently identified [28].…”

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confidence: 99%

“…In Rag -/-DN3a thymocytes, a functionally relevant discrete chromatin loop mediated by CTCF-bound INT1/2 and CTCF-bound TEAp has been recently identified [28]. Active Eδ is present within this chromatin loop attached to the Trdd and Trdj gene segments constituting a recombination center capable of recruiting the distant Trdv gene segments in DN2/3a thymocytes [5,28]. In addition to CTCF, other factors are required for loop formation because it is not present in B lymphocytes where occupancy of the relevant CTCF sites remains intact [28].…”

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confidence: 99%

“…In Rag -/-eDP thymocytes, binding of the pre-TCR inducible TFs to Eα triggers the formation of a chromatin hub through the physical interactions of the Eα-bound TFs, TFs bound to the promoters associated with the most 3´-Trav/Trdv gene segments and TEAp, and the CTCF bound to HS-1´ and each Eα-dependent promoter (Figure 3) [27,31]. This chromatin hub creates an additional recombination center at the 3´-Trav/Trdv and 5´-Traj gene segments to activate the primary Tcra VJ recombination in DP thymocytes [5]. …”

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confidence: 99%

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Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Hernández-Munaín¹,

Casal²,

Juanes³

et al. 2016

J Clin Cell Immunol

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The combined T-cell receptor α and δ locus, Tcra/Tcrd, encodes the TCRα and TCRδ chains of the αβ or γδ T-cell receptors (TCRαβ and TCRγδ), respectively, which define the two distinct T-cell lineages, αβ and γδ T lymphocytes. Like other antigen receptor loci, this locus must recombine its variable (V), diversity (D), and joining (J) gene segments to generate a diverse range of TCR that allow vertebrates to respond to an unlimited number of antigens. The Tcra/Tcrd germline transcription and subsequent V(D)J gene segment rearrangements are strictly regulated by two distant transcriptional enhancers, Eα and Eδ, respectively, during thymocyte development. Once the Tcra locus is productively rearranged, it is assumed Eα remains active for the transcription of the rearranged locus and the expression of the functional TCRα chain in αβ T lymphocytes. However, our recent experiments have shown Eα is significantly inhibited during the final stage of thymocyte development, concomitantly with the expression of the rearranged Tcra locus, and remains inhibited in αβ T lymphocytes. These results imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T lymphocytes. Interestingly, Eα is essential for the normal expression of the rearranged Tcrd locus in γδ T lymphocytes. In this review, the current knowledge about the regulation of Tcra/Tcrd germline transcription and gene segment rearrangement during thymocyte development and the possible mechanisms for transcription of the rearranged Tcra locus in mature αβ T lymphocytes are discussed. The knowledge of the detailed mechanisms involved in the regulation of transcription at the Tcra/Tcrd locus by distant enhancers is important to understand the cases in which deregulation this process results in disease. Keywords: Transcription; T-cell receptor; V(D)J recombination; Enhancer Abbreviations:A Temporal Control of TCR Gene RearrangementsDuring thymic T-cell development (Figure 1), early T-cell progenitors (ETP) arising from fetal liver or bone marrow enter to the thymus, where they mature progressively through different stages that can be distinguished based on the expression of the CD4 and CD8 surface markers: CD4-CD8-double-negative (DN) thymocytes, immature single-positive (ISP) CD8 + thymocytes, CD4 + CD8 + doublepositive (DP) thymocytes, and CD4 + or CD8 + single-positive (SP) thymocytes [1]. Among the DN thymocyte population, four subpopulations can be further distinguished based on the expression of CD25 and CD44 surface markers: DN1 (CD44 + CD25 -), DN2 (CD44 + CD25 + ), DN3 (CD44 -CD25 + ), and DN4 (CD44 -CD25 -) thymocytes. In addition, two DN3 subpopulations can be distinguished based on the expression of CD27: DN3a (CD27 low ) and DN3b (CD27 high ) thymocytes [2]. Furthermore, two DP thymocyte populations can be distinguished based on the expression of CD71: early DP (eDP) (CD71 + ) and late DP (lDP) (CD71 -) thymocytes [3]. For αβ T-cell development, thymocytes transition from DN1 to SP thymocytes by matu...

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Section: Regulatory Cis-elements Present At the Tcra/tcrd Locusmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Hernández-Munaín¹,

Casal²,

Juanes³

et al. 2016

J Clin Cell Immunol

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

Anderson

Rocha

2022

WIREs Mechanisms of Disease

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γδ T cells are widely distributed throughout mucosal and epithelial cell‐rich tissues and are an important early source of IL‐17 in response to several pathogens. Like αβ T cells, γδ T cells undergo a stepwise process of development in the thymus that requires recombination of genome‐encoded segments to assemble mature T cell receptor (TCR) genes. This process is tightly controlled on multiple levels to enable TCR segment assembly while preventing the genomic instability inherent in the double‐stranded DNA breaks that occur during this process. Each TCR locus has unique aspects in its structure and requirements, with different types of regulation before and after the αβ/γδ T cell fate choice. It has been known that Runx and Myb are critical transcriptional regulators of TCRγ and TCRδ expression, but the roles of E proteins in TCRγ and TCRδ regulation have been less well explored. Multiple lines of evidence show that E proteins are involved in TCR expression at many different levels, including the regulation of Rag recombinase gene expression and protein stability, induction of germline V segment expression, chromatin remodeling, and restriction of the fetal and adult γδTCR repertoires. Importantly, E proteins interact directly with the cis‐regulatory elements of the TCRγ and TCRδ loci, controlling the predisposition of a cell to become an αβ T cell or a γδ T cell, even before the lineage‐dictating TCR signaling events. This article is categorized under: Immune System Diseases > Stem Cells and Development Immune System Diseases > Genetics/Genomics/Epigenetics

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Changes of T Cell Receptor (TCR) αβ Repertoire in the Face of Aging and Persistent Infections

Smithey

Nikolich‐Žugich

2017

Handbook of Immunosenescence

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Aging is associated with profound dysfunction in T cell responses, leading to increased susceptibility to infection. One potential factor underlying this susceptibility is the decrease in output of new naïve TCRαβ T cells from the aging thymus that, coupled to reduced peripheral T cell maintenance later in life, leads to a decline in αβ T lymphocyte numbers with aging (Note that much less is known about maintenance and importance of diversity within the TCRγδ and other specialized, TCR-restricted populations of T cells, which are not the topic of this chapter). In mouse studies where experimental T cell tracking is possible, the maintenance of naive T cells over a lifespan was found to be asymmetricalsome clonotypes were found to have a competitive survival advantage over others. However, the clonotypes that survived into old age did not necessarily provide the best protection against infectious challenge. Understanding how aging impacts both the naïve and primed/elicited T cell repertoires, and how naïve T cells are maintained over the lifespan remains a critical challenge to understanding the decline of T cell immunity with aging. Here we review what is currently known about the mechanisms that generate and maintain TCRαβ repertoire diversity, and how TCR repertoires change over the lifespan. We hope to emphasize gaps in our understanding of T cell immunity, specifically when considered in the context of the diverse microbial environment that we experience over a lifetime.

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Chromatin Dynamics and the Development of the TCRα and TCRδ Repertoires

Cited by 54 publications

References 218 publications

Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

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

Changes of T Cell Receptor (TCR) αβ Repertoire in the Face of Aging and Persistent Infections

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