Enforcing order within a complex locus: current perspectives on the control of V(D)J recombination at the murine T‐cell receptor α/δ locus

Krangel, Michael S.; Carabaña, Juan; Abbarategui, Iratxe; Schlimgen, Ryan; Hawwari, Abbas

doi:10.1111/j.0105-2896.2004.00155.x

Cited by 83 publications

(88 citation statements)

References 71 publications

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“…Interestingly, the gene segment corresponding to V␣8.4 has been mapped to the central region of the TCRAD locus in close vicinity to the J␣ cluster (4). Therefore, the increased frequency of V␣8.4 containing TCR complexes in NICA rats is in agreement with the notion that impaired rearrangement favors the representation of central gene segments (35). Although correlative only, this finding suggests that reduced RAG expression during the DP stage impairs secondary rearrangements at the TCRAD locus and thereby alters the T cell repertoire.…”

Section: Pre-tcr Signaling Affects Re-expression Of the Rag Enzymes Asupporting

confidence: 85%

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

Brandt

Kwon

Hünig

et al. 2005

The Journal of Immunology

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Notch1 is involved in directing cell fate decisions in a variety of developmental scenarios. Extending previous experiments in mice, we generated transgenic rats expressing the intracellular domain of Notch1 in the thymus. Importantly, this leads to sustained expression of the pre-TCR throughout thymocyte development, accompanied by a reduction of αβTCR complexes. In addition, re-expression of RAG-1 and RAG-2 in TCRβ+ cells is impaired, and the Vα repertoire is altered. Consequently, thymocytes in transgenic rats do not undergo positive selection and largely fail to progress to the single positive stage. According to our model, the previously reported effects of Notch1 on the CD4/CD8 cell fate decision may be explained by a differential sensitivity of the two lineages toward altered TCR signaling.

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Section: Pre-tcr Signaling Affects Re-expression Of the Rag Enzymes Asupporting

confidence: 85%

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

Brandt

Kwon

Hünig

et al. 2005

The Journal of Immunology

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“…During the DN stage of development, the Tcrb locus rearranges its variable (V), diversity (D), and joining (J) gene segments by the process of V(D)J recombination (1). Expression of a functional T cell receptor (TCR)␤ protein leads to the development of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes, which then rearrange the Tcra locus (2). Tcra locus rearrangement is unique in several respects.…”

mentioning

confidence: 99%

Role for rearranged variable gene segments in directing secondary T cell receptor α recombination

Hawwari

Krangel

2007

Proc. Natl. Acad. Sci. U.S.A.

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During the recombination of variable (V) and joining (J) gene segments at the T cell receptor ␣ locus, a V␣J␣ joint resulting from primary rearrangement can be replaced by subsequent rounds of secondary rearrangement that use progressively more 5 V␣ segments and progressively more 3 J␣ segments. To understand the mechanisms that target secondary T cell receptor ␣ recombination, we studied the behavior of a T cell receptor ␣ allele (HY␣) engineered to mimic a natural primary rearrangement of TRAV17 to J␣57. The introduced V␣J␣ segment was shown to provide chromatin accessibility to J␣ segments situated within several kilobases downstream and to suppress germ-line J␣ promoter activity and accessibility at greater distances. As a consequence, the V␣J␣ segment directed secondary recombination events to a subset of J␣ segments immediately downstream from the primary rearrangement. The data provide the mechanistic basis for a model of primary and secondary T cell receptor ␣ recombination in which recombination events progress in multiple small steps down the J␣ array. Expression of a functional T cell receptor (TCR)␤ protein leads to the development of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes, which then rearrange the Tcra locus (2). Tcra locus rearrangement is unique in several respects. First, primary Tcra rearrangements use J␣ segments at the 5Ј end of the 65-kb J␣ array (3-6). Second, primary rearrangements can be replaced by secondary rearrangements that use progressively more 3Ј J␣ segments until a selectable ␣␤ TCR is generated (7-12). Third, rearrangement occurs on both alleles in a relatively synchronous manner without allelic exclusion (10,13,14). Rearrangement terminates by down-regulation of recombinase expression as a result of positive selection or by apoptosis if positive selection fails to occur (6,(15)(16)(17). Positive selection allows the development of CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive thymocytes, which then exit the thymus to the circulation. Although much is known about primary rearrangements, little is known about the mechanisms that control secondary rearrangements.Multiple regulatory elements are known to activate and control accessibility to the J␣ array (composed of 61 J␣ segments) in DP thymocytes. The Tcra enhancer (E␣) at the 3Ј end of the Tcra locus was shown by gene targeting to control all V␣-to-J␣ rearrangements and to maintain the J␣ array in an accessible state in DP thymocytes (18,19). However, E␣-dependent accessibility also requires the activation of germ-line promoters within the J␣ array. The T early ␣ (TEA) and J␣49 promoters were identified at the 5Ј end of the J␣ array and were shown to account for the majority of primary rearrangements (20,21). Rearrangements in mice lacking both promoters were substantially reduced across the entire 5Ј region, recovering to normal levels by J␣37 (21). Two models have been proposed to explain the targeting of primary and secondary rearrangements (6,13,20). The ''developmental windows'' model suggests that sequential activation o...

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“…In both humans and mice, the TCRA and TCRD genes are encoded within the same locus (TCRA/D; Krangel et al, 2004). The mouse Tcra/d locus lies on chromosome 14, with the C exons, which lie at the 3 (telomeric) end of Tcra/d, being preceded upstream by 60 J segments (Krangel et al, 2004;Fig.…”

Section: Recurrent Amplification Upstream Of Tcra/d Locus In Atm-defimentioning

confidence: 99%

“…The mouse Tcra/d locus lies on chromosome 14, with the C exons, which lie at the 3 (telomeric) end of Tcra/d, being preceded upstream by 60 J segments (Krangel et al, 2004;Fig. S1).…”

Section: Recurrent Amplification Upstream Of Tcra/d Locus In Atm-defimentioning

confidence: 99%

“…We also found that Bcl11b, which in some ATM deficient thymic lymphomas (Callén et al, 2007;Huang et al, 2007;Liyanage et al, 2000). As most develop ing T lymphocytes in mice that rearrange the Tcra locus do so on both alleles and delete the Tcrd locus (Krangel et al, 2004), the hypothesis that recurrent chromosome 14 translocations in Atm / thymic lymphomas involve aberrant Tcra locus re arrangements would imply that these tumors should fre quently show bi allelic deletions of, at least, a portion of J and complete deletion of the C region. To test this, we ana lyzed high density CGH data in and around the vicinity of Tcra/d locus and found that 16 out of 18 ATM deficient thymic lymphomas, in fact, retained the C region (Fig.…”

Section: Molecular Characterization Of T(12;14) Translocations In Atmmentioning

confidence: 99%

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ATM-deficient thymic lymphoma is associated with aberranttcrdrearrangement and gene amplification

Zha¹,

Bassing²,

Sanda³

et al. 2010

J Cell Biol

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Enforcing order within a complex locus: current perspectives on the control of V(D)J recombination at the murine T‐cell receptor α/δ locus

Cited by 83 publications

References 71 publications

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

Role for rearranged variable gene segments in directing secondary T cell receptor α recombination

ATM-deficient thymic lymphoma is associated with aberranttcrdrearrangement and gene amplification

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