Developmental T cell receptor gene rearrangements: Relatedness of the α/β and γ/δ T cell precursor

Thompson, Susan D.; Manzo, Andrea; Pelkonen, Jukka; Larché, Mark; Hurwitz, Julia L.

doi:10.1002/eji.1830210824

Cited by 38 publications

(14 citation statements)

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“…thymocytes which have concomitantly rearranged a and 6 genes cannot mature further and die out before they are positively selected? This seems unlikely as the concomitant d 6 rearrangement pattern is extremely frequent throughout thymic development (fetal [see Table 11 and adult [21]). In fact, it has been demonstrated in at least two cases that a T cell with a concomitant d 6 rearrangement can mature to a functional T cell [9,23,241.…”

Section: Discussionmentioning

confidence: 98%

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Restricted onset of T cell receptor α gene rearrangement in fetal and neonatal thymocytes

et al. 1996

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The initial T cell receptor (TCR) alpha gene rearrangements were analyzed in fetal and neonatal thymocyte hybridomas by Southern blotting. Interestingly, in 30% of all thymocyte hybridomas and in all fetal day 16 thymocyte hybridomas the most proximal J alpha 50 (psi J alpha) gene was rearranged. This rearrangement was found on one chromosome only and mostly in association with a delta rearrangement on the homologous chromosome. J alpha 50 was rearranged to multiple target genes based on the variable size of the restriction fragments. In addition, delta rearrangement was found with a concomitant alpha rearrangement in the majority of hybridomas and it was not only associated with J alpha 50 but with several other rearranged J alpha genes as well. Our results clearly demonstrate that T cell precursors are not pre-committed to either delta or alpha rearrangement but a flexible progenitor responds to multiple regulatory signals during T cell differentiation and they do not support the notion that delta rec-psi J alpha rearrangement is required for cell commitment to TCR alpha gene rearrangement.

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Section: Discussionmentioning

confidence: 98%

“…We have previously demonstrated that mature T cell hybridomas derived from the spleen taken soon after birth share the high frequency of 5 ' J a gene rearrangements identified among fetal thymocytes. Conversely, adult thymocyte and splenocyte hybridoma populations preferentially utilize 3 ' Ja genes in rearrangement events [21].…”

Section: Discussionmentioning

confidence: 99%

Restricted onset of T cell receptor α gene rearrangement in fetal and neonatal thymocytes

et al. 1996

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“…Because most T cells from both ab and cd lineages rearrange TCRc (but not necessarily TCRa, TCRb, or TCRd) at an early stage of their development, the TCRc gene is the ideal target for the detection of T-cell clonality in human lymphomas. 2,3,11,12 In the dog, the TCRc locus is well characterized, consisting of 4 V region segments (V1-V4), 6 J region segments (J1-J6), and 4 C region segments (C1-C4). 15 Clonality assessment of T-cell populations that target the TCRc gene first used restriction fragment length polymorphism (RFLP) and Southern blotting, 13 which is an efficient but laborious and timeconsuming approach.…”

Section: Introductionmentioning

confidence: 99%

Improved Polymerase Chain Reaction–Based Method to Detect Early-Stage Epitheliotropic T-Cell Lymphoma (Mycosis Fungoides) in Formalin-Fixed, Paraffin-Embedded Skin Biopsy Specimens of the Dog

Chaubert

Sattler

et al. 2010

J VET Diagn Invest

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Abstract. In the dog, early-stage epitheliotropic T-cell lymphoma (ETCL) can clinically and histologically mimic a large range of inflammatory dermatoses and often progresses rapidly to a more aggressive tumor stage. Early diagnosis of ETCL is essential to proceed with a specific oncologic therapy that is favorable for the prognosis. In the present study, an improved method for the detection of T-cell receptor gamma (TCRc) rearrangement was developed by designing a new set of consensus primers to amplify the different forms of rearranged canine TCRc gene sequences by polymerase chain reaction. The amplicons were analyzed by conventional polyacrylamide gel electrophoresis, which requires minimal specific equipment and may be performed in almost every pathology laboratory at low costs. The method proved to be highly specific and sensitive to detect early ETCL in formalin-fixed, paraffin-embedded biopsy specimens, providing an efficient tool for veterinary pathologists to distinguish early neoplastic from reactive cutaneous T-cell infiltrates (tumor-specific marker) or to discriminate T-cell lymphoma from B-cell lymphomas or nonlymphoid neoplasms (T-cell lineage marker). By direct sequencing analysis of amplified TCRc gene sequences, ETCL was found to rearrange exclusively the joining (J) 4 region, which suggests specific biology for primary cutaneous T-cell lymphomas. Also, a novel (seventh) functional J region in the TCRc gene, localized approximately 2.3 kb upstream of J5, was identified.

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“…1A) (11). As a result of the genomic architecture of the ␣/␦ locus, TRAV-TRAJ rearrangements excise the TCR␦ gene segments; therefore, the developmental timing of TCR␣/␦ rearrangements must be tightly linked to the ␣/␤ versus ␥/␦ T cell fate decision (12). The repertoire of particular TRAV and TRDV gene segments remains restricted in the absence of selection, strongly suggesting that these restrictions occur at the level of V(D)J recombination (13).…”

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Differential utilization of T cell receptor TCRα/TCRδ locus variable region gene segments is mediated by accessibility

Lee

Alt

Reyes

et al. 2009

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

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epigenetic regulation ͉ T cell development ͉ VDJ recombination A ssembly of antigen receptor variable gene segments through V(D)J recombination generates the remarkable diversity and specificity of the immune system. To initiate this reaction, the RAG-1 and RAG-2 proteins (RAGs) introduce a DNA double-strand break between a pair of V, D, or J coding gene segments and their flanking recombination signal sequences (RSs) (1, 2). RSs are composed of a conserved heptamer and nonamer, separated by a relatively nonconserved 12-or 23-bp spacer. V(D)J recombination only occurs between a pair of gene segments flanked by, respectively, a 12-RS and a 23-RS, a restriction known as the 12/23 rule (3). Successful V(D)J recombination leads to production of a functional B cell receptor in B cells, and either an ␣/␤ or ␥/␦ receptor in T cells. As expression of appropriate antigen receptor chains is closely associated with the general program of lymphocyte development, control of V(D)J recombination is important to ensure that only appropriate rearrangement events occur in a developing B or T cell (4-6). Regulation of V(D)J recombination, therefore, takes place on several levels and involves factors both intrinsic and extrinsic to the respective antigen receptor loci (7,8).The T cell receptor (TCR)␣/␦ locus has a unique genomic organization and pattern of V(D)J recombination. V gene segments for both loci are found in 1 large cluster, with exclusive TRAV gene segments generally found toward the distal end of the cluster, TRADV gene segments (that rearrange efficiently with both TRDD and TRAJ gene segments) located in the middle of the cluster, and largely TRDV gene segments lying toward the proximal end of the cluster (9). Two TRDD gene segments are linked closely to 2 TRDJ segments, and TCR␦ locus rearrangements typically employ both TRDD segments to form V(DD)J rearrangements on both alleles. Therefore, in developing thymocytes, the TCR␦ locus undergoes 3 distinct joining events: TRDV-5ЈTRDD1, 3ЈTRDD1-5ЈTRDD2, and 3ЈTRDD2-TRDJ rearrangements (10). Approximately 60 TRAJ gene segments are arrayed downstream of the TRDD/TRDJ segments and rearrange directly with the TRAV gene segments to generate TRAV-TRAJ joins (Fig. 1A) (11). As a result of the genomic architecture of the ␣/␦ locus, TRAV-TRAJ rearrangements excise the TCR␦ gene segments; therefore, the developmental timing of TCR␣/␦ rearrangements must be tightly linked to the ␣/␤ versus ␥/␦ T cell fate decision (12). The repertoire of particular TRAV and TRDV gene segments remains restricted in the absence of selection, strongly suggesting that these restrictions occur at the level of V(D)J recombination (13). However, it remains unclear whether exclusive TRAV and TRDV gene segments are identified as such only on the basis of differential accessibility of RS DNA to the RAGs, or whether there are unique structural features, such as intrinsic RS preferences, which distinguish them with respect to rearrangement potential.Differential accessibility of RSs to the RAGs as a mechanism o...

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Developmental T cell receptor gene rearrangements: Relatedness of the α/β and γ/δ T cell precursor

Cited by 38 publications

References 38 publications

Restricted onset of T cell receptor α gene rearrangement in fetal and neonatal thymocytes

Restricted onset of T cell receptor α gene rearrangement in fetal and neonatal thymocytes

Improved Polymerase Chain Reaction–Based Method to Detect Early-Stage Epitheliotropic T-Cell Lymphoma (Mycosis Fungoides) in Formalin-Fixed, Paraffin-Embedded Skin Biopsy Specimens of the Dog

Differential utilization of T cell receptor TCRα/TCRδ locus variable region gene segments is mediated by accessibility

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