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The Journal of Immunology, 2003, 171: 524-527.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: TCR {delta} Gene Is Frequently Rearranged in Adult B Lymphocytes 1

Ondrej Krejci*,{dagger}, Zuzana Prouzova*, Ondrej Horvath§, Jan Trka*,{dagger} and Ondrej Hrusak2,*,{ddagger}

* Childhood Leukemia Investigation Prague, and {dagger} 2nd Department of Pediatrics and {ddagger} Institute of Immunology, Charles University 2nd Medical School, Praha, Czech Republic; and § Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
TCR gene rearrangement generates diversity of T lymphocytes by V(D)J recombination. Ig genes are rearranged in B cells using the same enzyme machinery. Physiologically, TCR gene is postulated to rearrange exclusively in T lineage, but malignant B precursor lymphoblasts contain rearranged TCR genes in most patients. Several mechanisms by which malignant cells break the regulation of V(D)J recombination have been proposed. In this study we show that incomplete TCR {delta} rearrangements V2-D3 and D2-D3 occur each in up to 16% alleles in B lymphocytes of all healthy donors studied, but complete VDJ rearrangement was negative at the sensitivity limit of 1%. Data are based on real-time quantitative PCR validated by PAGE and sequencing of the cloned products. Therefore, TCR genes rearrange not exclusively in T lineage. This study opens up further questions regarding the exact extent of the "cross-lineage" TCR or Ig rearrangements in normal lymphocytes, specific subsets in which the cross-lineage rearrangements occur, and the physiological importance of these rearrangements.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
AV(D)J recombination generates diversity of both B and T lymphocytes via the assembly of either Ig or TCR genes, respectively. Although the recombination-activating gene (RAG) 3-1 and RAG-2 machinery is identical, the lineage specificity of V(D)J recombination is strictly regulated. Thus, complete rearrangement and expression of either Ig or TCR genes occurs specifically either in B or T lymphocytes, respectively (1). It is postulated that the strict and hierarchical regulation of V(D)J gene recombination is achieved by a differential accessibility of Ig and TCR gene chromatin in B and T cells, respectively (2, 3). It is generally believed that B cells exclusively rearrange Ig genes, but not TCR genes, and vice-versa for T cells (4).

Conversely, malignant B cell precursors contain cross-lineage TCR gene rearrangement in over 90% of children with precursor B acute lymphoblastic leukemia (ALL) (5). In leukemias, the most frequent among the known cross-lineage TCR gene rearrangements are V{delta}2-D{delta}3 and D{delta}2-D{delta}3 of the TCR {delta} gene locus, which physiologically codes for TCR {delta}-chain (5). Both V{delta}2-D{delta}3 and D{delta}2-D{delta}3 (occurring in 67% and 13% of precursor B ALL cases, respectively) represent incomplete TCR {delta} gene rearrangements, because J{delta} loci are only rarely involved (6).

The reasons why cross-lineage TCR {delta} rearrangements occur in malignant B precursors have not been explained. Indeed, nonmalignant fetal B precursors were shown not to rearrange TCR {delta} genes (7). At least four different mechanisms of the deregulation have been suggested (5, 7), none of which has been formally proven or dismissed. Surprisingly, the lineage fidelity of the TCR {delta} gene rearrangement has not been tested in normal B cells. Therefore, we studied the TCR{delta} rearrangements—most frequently found in B precursor ALL—in peripheral blood B lymphocytes isolated from healthy donors.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mononuclear cells were isolated from peripheral blood of healthy volunteers by Ficoll-Paque (density 1.077 g/ml; Pharmacia Biotech, Uppsala, Sweden) density centrifugation. Cells were stained either with FITC-labeled anti-CD19 mAb or with a combination of FITC-labeled anti-CD3 and PE-labeled anti-CD19 (Immunotech, Marseille, France). CD19-positive cells were sorted on FACSVantageSE cell sorter (BD Biosciences, San Jose, CA). The purity of sorted cells was verified by reanalysis of the samples on the cell sorter (98 ± 1.3% CD19+ cells and 0.26 ± 0.34% CD3+ cells in sorted B fraction). Genomic DNA from sorted cells was isolated by QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany). DNA was stored in -20°C before processing. DNA from cell lines HT29 (colon carcinoma), BT474 (breast carcinoma), HeLa and AC (XX cells from amniocentesis) served as a negative control. Manipulation with volunteer donor and patients cells was approved with institutional ethical board.

Real-time quantitative (RQ)-PCR was performed in the LightCycler rapid thermal cycler system (Roche Diagnostic, Mannheim, Germany). Forward primers V{delta}2-5' and D{delta}2-5' as previously described (8) were placed in TCR{delta}V2 exon and in TCR {delta} intronic sequence preceding D{delta}2 segment, respectively. Reverse primer RDD3-cons4 and hydrolyzation probe T-D{delta}3-cons2 labeled with fluorescein and N,N,N,N'-tetramethyl-6-carboxyrhodamine placed in TCR{delta}D3 exon and adjacent intron sequence were previously described (6). Reverse primer R-JD{delta}1-cons1 and probe T-J{delta}1-cons1 used for amplification of V{delta}2-D{delta}-J{delta}1 complete rearrangement were placed in TCR {delta} J1 exon and 3' adjacent intronic sequence (van Dongen et al., unpublished observations and Fig. 1). PCR amplification was conducted in 1x reaction buffer (20 mmol/L Tris-HCl, pH 8.4, 50 mmol/L KCl, 3.0 mmol MgCl2) containing 200 µmol/L of each dNTP, 0.5 µmol/L of each primer, 0.2 µmol/L of the probe, BSA 5 µg/reaction and 1 U of Platinum Taq DNA Polymerase (Life Technologies, Carlsbad, CA) in a final reaction volume of 20 µl. For each PCR, 1 µl DNA at concentration 0.01–0.2 µg/µl was used. The cycling conditions were as follows: initial denaturing 94°C, 2.5 min, 45 cycles of denaturing 95°C 5 s; annealing-extension 68°C (V{delta}2-D{delta}3 system), 64°C (D{delta}2-D{delta}3 system) 1 min or 66°C 20 s (V{delta}2-J{delta}1 system). {beta}2-microglobulin ({beta}2m) housekeeping gene was used to normalize the DNA concentration and quality. System for quantification of {beta}2m was previously described (9). Quantification was performed with LightCycler Software version 3.5 (Idaho Technology, Salt Lake City, UT). Briefly, the starting concentration of template was measured against dilution series of positive control DNA in buffered water. REH cell line and B precursor ALL and T lineage ALL patient samples bearing monoclonal rearrangements served as a positive control for V{delta}2-D{delta}3, D{delta}2-D{delta}3, and V{delta}2-J{delta}1 systems, respectively. Positive control was considered to bear one monoclonal rearrangement per cell and stated to contain 100% alleles. Each sample was run in duplicate. The amount of rearranged alleles is calculated from the dilution curve and the DNA amount was normalized using a housekeeping gene {beta}2m. PAGE analysis of PCR products was performed on 5% polyacrylamide gel (Sigma-Aldrich, St. Louis, MO).



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  		FIGURE 1. TCR {delta} locus scheme. V{delta}2-D{delta}3, D{delta}2-D{delta}3, and V{delta}2-J{delta}1 rearrangements are placed below the germline sequence. Position of primers and hydrolyzation probes are indicated in rearranged loci. The {delta}REC and {psi}J{alpha} segments marked () flank TCR {delta} locus and they are involved in TCR {delta} deletion.

 
Cloning of PCR products was performed with TOPO TA Cloning kit (Invitrogen, Carlsbad, CA). Plasmid DNA from 35 single colonies (five to six colonies per donor) was isolated by alkaline lysis miniprep (10, 11). Presence of V{delta}2-D{delta}3 insert was verified by PCR using the identical primers. Thirteen colonies with a clear monoclonal band on PAGE were selected for sequencing. Sequencing was performed in the ABI PRISM 310 Genetic Analyzer with BigDye Primer v3.0 Sequencing kit (Applied Biosystems, Foster City, CA).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
TCR {delta} gene loci rearrange in B cells

Preliminary RQ-PCR analysis of purified B cells of two different donors showed a clear positivity of the rearranged TCR {delta} gene, which corresponded to 8.3–15.4% alleles. A subsequent analysis of purified B cells from six different donors showed rearrangement V{delta}2-D{delta}3 in 9.6–15.0% alleles and D{delta}2-D{delta}3 in 6.5–16.0% alleles (Fig. 2). No amplification signal was detected in the nonlymphoid DNA samples during the entire RQ-PCR analysis. The PCR products were reanalyzed by PAGE. In all blood B cell specimens, the products contained oligoclonal to polyclonal DNA (Fig. 3). A positive control, REH lymphoblastic cell line and a sample from an ALL patient with one TCR {delta} rearranged allele, showed a clear monoclonal band. The fact that the patterns of PCR products differ among the donors virtually excludes false positivity due to contamination by PCR products. All tested nonlymphoid cells were negative (Fig. 3). It should be noted that our system detects only an incomplete TCR {delta} rearrangement because rearrangement of any J{delta} locus to the TCR D{delta}3 would prevent binding of the reverse primer (Fig. 1). Therefore, an incomplete rearrangement of TCR {delta} is present in peripheral B lymphocytes.



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  		FIGURE 2. Percentage of V{delta}2-D{delta}3 and D{delta}2-D{delta}3 rearranged alleles in sorted cells. Frequency of V{delta}2-D{delta}3 (•) and D{delta}2-D{delta}3 ({circ}) rearranged alleles in sorted CD19+ (B cells) or CD3+ (T cells), and nonlymphoid cells. The percentage is derived from a dilution curve of a positive control (100%) bearing monoclonal rearrangement. REH cell line (with V{delta}2-D{delta}3 rearrangement) and primary lymphoblasts (with D{delta}2-D{delta}3 rearrangement) from a patient with ALL were used as a positive control.

 


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  		FIGURE 3. PAGE analysis of V{delta}2-D{delta}3 (A) and D{delta}2-D{delta}3 (B) rearrangements. Peripheral B lymphocyte samples are shown in lines 1–6, nonlymphoid samples are in lines 7–10. Positive control REH cell line and ALL patient samples for V{delta}2-D{delta}3 and D{delta}2-D{delta}3, respectively, are shown (+). MW, 100 bp molecular marker.

 
Low level of incomplete TCR {delta} rearrangements in T cells

The sorted CD3+ cells were analyzed using the identical approach as described in CD19+ cells. As expected, the RQ-PCR signal was low and corresponded to 1.2–8.5% and 0.9–7.2% V{delta}2-D{delta}3 and D{delta}2-D{delta}3 rearranged alleles, respectively (Fig. 2). TCR {delta} gene rearranges in most developing T cells, together with TCR {beta} and TCR {gamma} genes (12). Nonetheless, only a subset of cells that rearranged their TCR {delta} gene would be detected in our system. Of TCR{gamma}{delta}+ cells, only those with incomplete TCR V{delta}2-D{delta}3 or TCR D{delta}2-D{delta}3 would generate a signal. Of TCR{alpha}{beta}+ cells, only those with the recent thymic emigrant phenotype could be positive if they contain an incompletely rearranged TCR {delta} allele in an excision circle. Alternatively, the TCR{alpha}{beta}+ cells with just one TCR {alpha} allele rearranged together with the incomplete TCR {delta} rearrangement on the other allele could be positive (Fig. 1). Such cells are rare because most TCR{alpha}{beta}+ cells rearrange both TCR {alpha} alleles and delete the respective TCR {delta} genes (13, 14, 15).

Sequencing confirms TCR {delta} rearrangements

We have cloned RQ-PCR V{delta}2-D{delta}3 products in Escherichia coli to obtain monoclonal copies of incompletely rearranged TCR {delta} locus genes suitable for sequencing. Plasmid DNA from 13 single colonies was sequenced. In donors 2 and 5, two colonies had identical sequences (Table I). All 11 different colonies selected from six peripheral B lymphocyte samples contained a sequence of V{delta}2-D{delta}3 rearrangement. Nucleotides (3–18 bp) were inserted in each sequence. Palindromic as well as nongermline encoded nucleotides could be identified (Table I). Deletions of nucleotides from 3'-end of V segment and 5'-end of D segment were presented in seven and three clones, respectively. In three different clones from different donors, a sequence identical with a D2 segment was detected within the inserted region (Table I). This implies that two D segments (D{delta}2 and D{delta}3) are involved in the V-D rearrangement. The V{delta}2-D{delta}2-D{delta}3 sequence is observed in part of the physiological TCR{gamma}{delta}+ cells (16).


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  		Table I. Sequence of TCRD V{delta}2-D{delta}3 rearrangement in CD19+ cellsa

 
No V{delta}2D-J{delta}1 rearrangements of TCR {delta} gene in normal B cells

We wanted to determine whether complete TCR {delta} rearrangements take place in comparable fractions of B cells as the incomplete V-D(-D) rearrangements. Therefore, we analyzed five specimens of sorted CD19+ cells in an RQ-PCR system with primers in the V{delta}2 and J{delta}1 loci. The CD3+ contamination of the sorted CD19+ was 0.00–0.19% (optical scatter of cells); whether all events including noncellular debris/aggregates were considered, the total percentage of CD3+ events was 0.25–0.5%. Because nonvital remnants of a CD3+ cell could contain amplifiable DNA, we consider any positivity below 1% as potentially caused by the contaminating cells. With the sensitivity limit of 1%, we could not detect positivity in any of the five specimens. Moreover, four of five specimens were negative RQ-PCR even below 1% in the V{delta}2D-J{delta}1 system. One specimen revealed positivity at 0.5%. This level could be attributed to the traces of CD3+ cells among the sorted B cells. Thus, B cells either do not contain completely rearranged V{delta}2D-J{delta}1 gene segments of TCR {delta} at all or they do completely rearrange TCR {delta} at a very low level that is under our detection limit. We conclude that the amount of B cells with complete V{delta}2D-J{delta}1 TCR {delta} rearrangements is negligible compared with the frequent incomplete TCR {delta} rearrangement.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Under physiological conditions, TCR rearrangement has been thought to occur only in T lineage cells (4, 12). The cross-lineage rearrangement of TCR {delta} that occurs in most precursor B ALL has been a puzzling phenomenon. It was not clear how the malignant cells evaded the assumed stringent control of V(D)J recombination. The formal proof that physiological B cells do not rearrange TCR gene has not been presented. Nevertheless, several mechanisms of the evasion from the assumed regulation have been hypothesized (5, 7).

The same TCR genes that are commonly rearranged in malignant B lymphoblasts are studied in this report. They were shown positive in a portion of B lymphocytes of all donors tested. Presented data indicate that TCR {delta} rearrangements in leukemic B lymphoblasts are not an exclusive attribute of malignant cells but reflect TCR {delta} rearrangements occurring in physiological B lineage cells.

The presented sequencing data prove the involvement of the specific V{delta} and D{delta} loci. Moreover, the position of the junction as well as the insertion and deletion of nucleotides appears to follow the rules known from physiological V(D)J recombination (17). Therefore, these rearrangements seem to be performed by the normal V(D)J recombination machinery.

During the development of TCR{gamma}{delta}+ cells in adults, V{delta}2-D{delta} rearrangement is preferred, as can be deduced from the fact that V{delta}2+ cells prevail among peripheral TCR{gamma}{delta}+ cells (18). Experiments on transfected nonlymphoid cells have shown that both V{delta}2-D{delta}3 and D{delta}2-D{delta}3 could be enforced by introducing RAG1 plus RAG2 plus a member of the E-protein family (E2-2, E2A, or HEB). The same transfections were unable to enforce any rearrangement to the J loci (6). Thus, the rearrangements of the V and D loci appear to be under loose control compared with the regulation of the complete V(D)J rearrangement. This mechanism may be responsible for the cross-lineage rearrangement observed in this study.

The key factor that regulates the TCR or Ig gene rearrangements is the chromatin accessibility of these genes (19, 20, 21). Several molecular mechanisms are known that may be involved in "opening" the chromatin and maintaining it accessible for recombination machinery. These include histone hyperacetylation, CpG demethylation, recruitment of transcriptional coactivators, and domain-wide acetylation associated with chromosome repositioning in the nucleus (3, 19, 20, 22). The details of how the function of enhancers and promotors translates into chromatin accessibility are largely unknown. As shown in mice carrying the human artificial TCR {delta} minilocus, V{delta} can rearrange to D{delta} without the enhancer activity, whereas D{delta} to J{delta} rearrangement requires the enhancer to take place (21). Therefore, our findings indicate that B cells may contain the accessible TCR {delta} gene but they normally lack the E{delta} enhancer activity.

Theoretically, V{delta}-D{delta} rearrangement could take place at a common lymphoid progenitor and the TCR {delta} locus becomes inaccessible when the cell commits to B lineage. Alternatively, the V{delta}-D{delta} locus could be left accessible after the B lineage commitment and rearrangement may occur during the entire Ig gene recombination. The presence of inserted nucleotides indicates that TCR {delta} rearranges in the early phases of B cell development, in which TdT is active.

This study shows for the first time that the TCR and Ig genes are not exclusively rearranged in their respective lineage (T or B) PBLs in healthy humans. Discovery of the gaps in the regulation of TCR opens up further questions. Because we could detect only incomplete V-D rearrangement and not VD-J rearrangements, it appears that the lack of enhancer activity is a principal factor preventing complete TCR {delta} rearrangement and expression in B cells. Nevertheless, this hypothesis should be addressed directly. It should also be specified whether just TCR {delta} gene is loosely controlled and if so, if there is any biological impact of this result. In addition, the understanding of leukemogenesis in particular will benefit from knowing at which stages of development the cross-lineage rearrangements take place.


   Acknowledgments
 
We thank Dr. Krepelova and Dr. Sedlacek from the Institute of Biology and Medical Genetics, Charles University 2nd Medical School for sequencing and providing nonlymphoid DNA. We appreciate the comments of Dr. Horejsi and Dr. Bartunkova.


   Footnotes
 
1 This work was supported by projects MSMT 111300001, MSMT 111300003, IGA NE7430-3, and MZ00 000064203. Back

2 Address correspondence and reprint requests to Dr. Ondrej Hrusak, Childhood Leukemia Investigation Prague and Institute of Immunology, Charles University 2nd Medical School, V uvalu 84, 150 06 Praha 5, Czech Republic. E-mail address: Ondrej.Hrusak{at}lfmotol.cuni.cz Back

3 Abbreviations used in this paper: RAG, recombination-activating genes; RQ-PCR: real-time quantitative PCR; ALL, acute lymphoblastic leukemia; {beta}2m, {beta}2-microglobulin. Back

Received for publication February 27, 2003. Accepted for publication May 13, 2003.


   References
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 Introduction
 Materials and Methods
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 Discussion
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