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Ordered and Coordinated Rearrangement of the TCR Locus: Role of Secondary Rearrangement in Thymic Selection¹

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

	Abstract

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The Ag receptor of the T lymphocyte is composed of an heterodimer. Both - and -chains are products of the somatic rearrangement of V(D)J segments encoded on the respective loci. During T cell development, -chain rearrangement precedes -chain rearrangement. The mechanism of allelic exclusion ensures the expression of a single -chain in each T cell, whereas a large number of T cells express two functional -chains. Here we demonstrate evidence that TCR rearrangement is initiated by rearranging a 3' V segment and a 5' J segment on both chromosomes. Rearrangement then proceeds by using upstream V and downstream J segments until it is terminated by successful positive selection. This ordered and coordinated rearrangement allows a single thymocyte to sequentially express multiple TCRs with different specificities to optimize the efficiency of positive selection. Thus, the lack of allelic exclusion and TCR secondary rearrangement play a key role in the formation of a functional T cell repertoire.

	Introduction

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The development of the T cell in the thymus can be chronicled by the expression of the coreceptor, CD4 and CD8. Developing T cells start as CD4^-CD8^- (double-negative, DN)³ thymocytes, differentiate into CD4⁺CD8⁺ (double-positive, DP) stage, and finally become CD4⁺ or CD8⁺ (single-positive) mature T cells (1). The rearrangement of the TCR -chain occurs on a subset of DN thymocytes that are characterized as CD44^-CD25⁺ (2). The TCR -chain from a functionally rearranged gene pairs with the surrogate -chain, pT, to form preTCR, which has been shown to prevent further -chain rearrangement on the opposite allele (allelic exclusion) (3) and promote DN-to-DP transition (4, 5). This process, known as "-selection", limits each T cell to express a single TCR -chain (6).

In contrast, the rule of allelic exclusion is not strictly enforced during -chain rearrangement, as demonstrated by detection of two in-frame rearrangements in T cell tumor and hybridomas (7, 8) and simultaneous expression of transgenic and endogenous TCR -chain (3). Because the V and J segments are arranged in such a way that multiple rearrangements can occur on a single chromosome (9), this lack of allelic exclusion prompts the possibility of -chain secondary rearrangement, i.e., rearrangement of flanking V and J segments that deletes an existing rearranged VJ gene. Indeed, the presence of -chain secondary rearrangement is demonstrated both in vitro (10, 11, 12) and in vivo (13). In addition, as the rearrangement of the TCR -chain occurs at the DP stage and coincides with positive selection in which DP thymocytes bearing a TCR with an appropriate affinity to self-MHC/self-peptide are selected for maturation into single-positive mature T cells (14), it is suggested that the multiple -chains resulted from secondary rearrangement may enhance mature T cell production by allowing a single thymocyte to pursue multiple rounds of positive selection (12, 13, 15). However, the exact role of -chain secondary rearrangement during T cell development and TCR repertoire formation is still not clear.

To determine the role of -chain secondary rearrangement in T cell development, we sought for basic principles of -chain rearrangement that may correlate with the extent of secondary rearrangement in the thymus. By empirically defining these basic principles, our results strongly support that -chain secondary rearrangement is a critical component of T cell development.

	Materials and Methods

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Mouse

The knock-in (KI) mouse has been described (13). The KI/wild-type (wt) mice were generated by mating KI/KI homozygous mice with B6 mice that were purchased from The Jackson Laboratory (Bar Harbor, ME). BALB/c mice were also obtained from The Jackson Laboratory. All mice were housed in a specific pathogen-free facility at Washington University (St. Louis, MO). Handling of mice conforms to the guidelines of the Washington University Animal Facility.

T cell hybridoma

T cell hybridoma is generated by fusing Con A-activated splenic T cells from KI/wt mice with ^-- BW5147 thymoma (16, 17). On occasion, KI/wt splenocytes were panned with the mAb A2B4 that was specific for the KI -chain. The panned T cells were then sorted for the A2B4⁺ population and fused with ^-- BW5147 thymoma to generated KI⁺ hybridomas.

PCR assay

PCR were performed with Ampli-Taq (Roche Molecular Biochemicals, Indianapolis, IN) following the manufacturer’s specification. The KI PCR primers are 5'-GGGTGGGGTGGGATTAGATAAATG-3' and 5'-TGTACCCAGCACTCATCATAACCAGACTTC-3' (13). The cycling condition was 94°C for 5 min, followed by 30 cycles of 94°C for 45 s, 63°C for 30 s, and 72°C for 1 min. A 7-min incubation at 72°C was included at the end. The primers for J50 PCR were 5'-ATTGCATCTGGAGAGAGAGGAG-3' and 5'-TGTACCCACAGAAGTGAGCACC-3' (9). The cycling condition was 94°C for 5 min, followed by three cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s, with the annealing temperature decreased by 0.5°C between each cycle. It was then followed by 35 cycles of 94°C for 30 s, 59°C for 30 s, and 72°C for 30 s, and a 7-min 72°C incubation at the end. For J47 PCR, the primer sequences were 5'-CTGGAGGCAATAATAAGCTG-3' and 5'-TCCTAATTGTGCCCACATGGAAG-3' (9). The cycling condition was 94°C for 5 min, 30 cycles of 94°C for 45 s, 57°C for 30 s, and 72°C for 1 min, followed by a 7-min incubation at 72°C at the end. The quality of DNA was always checked by a control IL-2 PCR that amplified a 324-bp fragment from genomic DNA.

RT-PCR

Total thymocytes RNA from BALB/c mice were collected with an Ultraspec RNA isolation kit (Biotecx Laboratories, Houston, TX). Ten micrograms of RNA were used to generate cDNA with AMV-reverse transcriptase (Roche Molecular Biochemicals) in a 20-µl reaction following the manufacturer’s specifications. RT-PCR were performed using 3 µl cDNA in a 180-µl reaction with Ampli-Taq (Roche Molecular Biochemicals) following the manufacturer’s specifications. The RT-PCR products were then purified from agarose gel, cloned into pBluescript, and sequenced with a Big-Dye terminator kit (PE Applied Biosystems, Foster City, CA). The family-specific sense primers for each V family were: AV2, 5'-AGCAGCAGGTGAGACAAAGT-3' and 5'-AAGGAAGATGGACGATTCAC-3' (18); AV16, 5'-GTAGTGCAGAGCCCTTCCAT-3' (19); AV19, 5'-TCTGACAGAGCTCCAGATCAA-3' (15); and AV20, 5'-TGCTGTTGGTTCTGTGCCTG-3' and 5'-CAAAAGCGGCAAACACTTCT-3' (20). On occasion, a BamHI site was added at the 5' end of the primer to facilitate cloning of the product. The antisense C primer used was 5'-GCACATTGATTTGGGAGTC-3', and a XbaI site was sometimes added at the 5' end for cloning. When the BamHI and XbaI cloning sites were used, RT-PCR products containing J46 would not be cloned correctly because J46 contains an internal XbaI site. PCR were performed as described above with this cycling condition: 94°C for 5 min, followed by 30 cycles of 94°C for 45 s, 63°C for 30 s, and 72°C for 1 min. A 7-min incubation at 72°C was included at the end.

	Results

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Ordered usage of J segments for TCR rearrangement on both alleles

The mouse TCR locus consists of 100 V segments divided into 22 families (21), 50 J segments, and a single C gene (9). In studies comparing the rearrangement status of TCR loci, it was found that -chain rearrangement on both chromosomes usually rearranged to J segments at similar locations (7, 22). We confirmed this observation of "parallel" J usage by generating five T cell clones and surveying J usage from published TCR sequences (Table I) (7). One possible mechanism that can mediate this parallel J usage is to initiate rearrangement on both chromosomes at similar times during T cell development. In the initial rearrangement, 5' J segments are preferentially used. Further rearrangements use sequentially downstream J segments on the same chromosome. When a functionally rearranged gene from one of the two chromosomes is positively selected, rearrangement on both chromosomes ceases. This will leave the rearranged J on both chromosomes at similar locations on the J locus. To investigate this possibility, we used the previously described KI mouse in which a functionally rearranged VJ gene was inserted into the TCR locus such that the KI gene could be deleted by secondary rearrangement of the locus (13). In KI/wt mice, if the initiation and termination of rearrangement occurs simultaneously on both chromosomes, then the lack of rearrangement on the KI chromosome should be accompanied by the lack of rearrangement on the wt chromosome. Conversely, if the KI gene is deleted by secondary rearrangement on the KI chromosome, one or more rearrangements should also occur on the wt chromosome, resulting in rearrangement to downstream J segments (Fig. 1A).

View this table: [in this window] [in a new window]   Table I. Juxtaposed J usage on both chromosomes1

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Comparison of TCR rearrangement on the two loci of KI/wt mice. A, Schematic view of possible TCR rearrangements on both chromosomes from KI/wt mice. The KI gene insert contained from 5' to 3' a Neo-resistant gene, the rearranged VJ, and IgH 3' enhancer (13 ). B, PCR scheme for rearrangement status detection. DNA from expanded hybridoma clones was used in the following three PCR to detect the rearrangement status on both chromosomes. KI PCR detected the retention of the KI gene on the KI chromosome, J50 PCR detected the germline configuration on the wt chromosome, and J47 PCR detected rearrangement to J50-47 on the wt chromosome.

View this table: [in this window] [in a new window]   Table II. Synchronized -chain rearrangement on both chromosomes of KI/wt mice

Location-dependent and coordinated rearrangement of V/J segments

We postulate that the ordered J usage maximizes the number of TCRs that can be generated through TCR secondary rearrangement. Because V-J rearrangement deletes intervening sequences, the ordered 5' to 3' J usage must then be paired with an ordered V usage from 3' to 5' as illustrated in Fig. 2. As a result, a location-dependent coordinated rearrangement of 3' V to 5' J and 5' V to 3' J should be observed (Fig. 2). A similar scheme was suggested by Roth et al. based on Southern hybridization using a limited number of J probes (15). To further study this coordinated rearrangement, we selected four V families, AV2, AV16, AV19, and AV20 (Fig. 3). The choice of AV16 and AV20 families are critical because both families contain two members located at either extreme of the V locus; the J usage from the 5' and 3' V members can be compared with least possible bias because of their sequence homology. Therefore, by direct sequencing of cloned thymic TCR cDNA, the locations of the rearranged V and J segment will reveal whether there exists a location-dependent V-J coordinated rearrangement.

View larger version (26K): [in this window] [in a new window]   FIGURE 2. Schematic view of primary and secondary rearrangement of the TCR locus. The hatched box represents rearranged VJ in primary rearrangement, whereas the filled box represents rearranged VJ in secondary rearrangement.

View larger version (10K): [in this window] [in a new window]   FIGURE 3. Relative locations of AV2, AV16, AV19, and AV20 family members on the TCR V locus. The nomenclature of the V families follows Arden et al. (21 ). AV2 family (oval) has six members in BALB/c mice that are evenly distributed through out the V locus (18 25 31 32 ). AV16 (21 25 ) (rectangle) and AV20 (20 25 ) (spade) families both have two known subfamily members mapped to either extreme location. AV19 (hexagon) is a single member family located at the very 5' end of the V locus (25 ). The distance between segments did not reflect the actual distance on the V locus. *, Exact order of these three V segments was not known.

View this table: [in this window] [in a new window]   Table III. Location-dependent coordinated V-J rearrangement1

The analysis of AV16, which has two family members, is complicated in that only the sequence of the 3' V member has been reported (21, 25). Attempts to obtain the sequence of the 5' member by genomic PCR did not reveal any novel sequence (data not shown). Thus we are unable to distinguish whether the 5' or the 3' AV16 member is rearranged in our results. However, in all the clones that we obtained, the V region sequences matched with reported sequence of the 3' AV16 member (data not shown). In addition, most of the J segments used in these rearrangements were located at the 5' end of the J locus (Table III). Therefore, these results likely demonstrate a coordinated rearrangement of 3' V to 5' J, similar to the results from the AV20 family.

	Discussion

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The above results demonstrate a coordinated 3'V to 5' J and 5'V to 3' J rearrangement. Through this coordinated rearrangement the locus is optimized to express more -chains on a single chromosome via multiple rearrangements. In our analysis, we also found that 3' J (Table III) and 5' V (Table IV) were often under-represented. This under-representation may be yet another indication that multiple rearrangements have occurred on a single chromosome, as explained below. After multiple -chain rearrangements on the same chromosome, possible exhaustion of the V segments will prevent the remaining 3' J segments from being rearranged. Similarly, exhaustion of the J segments will prevent the rearrangement of the 5' most V segments. In a population of thymocytes, the likelihood of distal V and J segments to be rearranged should then be lower than that of proximal V and J segments. In contrast, if the V-J rearrangement is not coordinated, and occur only once on each chromosome, the proximal and distal V and J segments should be equally represented. Our data and previous reports (15, 22) clearly argue against this prediction.

The complete TCR repertoire is generated by somatic rearrangement of V(D)J segments, junctional diversity, and pairing of subunits, and is estimated to contain 10¹⁵ different specificities (26). In general, this repertoire must contain nonoverlapping sets of Ag-specific repertoires restricted to different MHC molecules. Because the MHC is the most polymorphic locus and contains at least 441 alleles in Caucasians alone (27), the TCR repertoire that is selectable by self-MHC must be a small fraction of the complete repertoire. Yet previous reports indicate that 5% of the thymocytes are selected for maturation (28). Several unique mechanisms of TCR rearrangement, i.e., the lack of allelic exclusion, frequent secondary rearrangements, ordered J usage, and location-dependent coordinated V-J rearrangement, may play critical roles in resolving this discrepancy as described in the following scheme.

During development, immature thymocytes expressing preTCR (pT/TCR) initiate -chain rearrangement using 3' V and 5' J segments on both chromosomes. The thymocyte bearing an TCR then undergoes positive selection for proper affinity for self-MHC/peptide complex (14). Successful positive selection down-regulates recombination-activating gene expression, thereby preventing further rearrangement (29). If positive selection is not successful, recombination-activating gene-mediated secondary rearrangement using flanking 5' V and 3' J will delete the rearranged VJ gene and produce another -chain that can be paired with the -chain. Thus multiple -chains from sequential rearrangements on both chromosomes allow a single immature thymocyte to attempt several rounds of thymic selection with different TCR specificities, which in turn greatly increase the probability for a thymocyte to be positively selected.

The ordered J usage, the location-dependent coordinated VJ rearrangement, and possibly the under-representation of distal V/J segments that we reported here provide the strongest support to date for the presence of multiple secondary rearrangements on a single chromosome. Taken together with previous reports (10, 12, 13, 15, 30), our results suggest that TCR secondary rearrangement is an important process for thymocyte development. They also suggest that multiple rearrangements during T cell development play a significant role in the formation of peripheral TCR repertoire.

	Acknowledgments

 
We thank A. Cheng and B. Sleckman for critical review of the manuscript. We also thank T. Cirrito, B. Edelson, M. Hughes, and A. Suri for helpful advises in preparing the manuscript.

	Footnotes

 
¹ This work is supported in part by the National Institutes of Health (to O.K.).

² Address correspondence and reprint requests to Dr. Osami Kanagawa, Department of Pathology and Immunology, Campus Box 8118, Washington University School of Medicine, St. Louis, MO 63110.

³ Abbreviation used in this paper: DN, double-negative; DP, double-positive; KI, knock-in; wt, wild type.

Received for publication September 18, 2000. Accepted for publication November 27, 2000.

	References

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1. Zuniga-Pflucker, J. C., M. J. Lenardo. 1996. Regulation of thymocyte development from immature progenitors. Curr. Opin. Immunol. 8:215.[Medline]
2. Penit, C., B. Lucas, F. Vasseur. 1995. Cell expansion and growth arrest phases during the transition from precursor (CD4^-8^-) to immature (CD4⁺8⁺) thymocytes in normal and genetically modified mice. J. Immunol. 154:5103.[Abstract]
3. Borgulya, P., H. Kishi, Y. Uematsu, H. von Boehmer. 1992. Exclusion and inclusion of and T cell receptor alleles. Cell 69:529.[Medline]
4. Fehling, H. J., A. Krotkova, C. Saint-Ruf, H. von Boehmer. 1995. Crucial role of the pre-T-cell receptor gene in development of but not T cells. [Published erratum appears in 1995 Nature 378:419.]. Nature 375:795.[Medline]
5. von Boehmer, H., I. Aifantis, O. Azogui, J. Feinberg, C. Saint-Ruf, C. Zober, C. Garcia, J. Buer. 1998. Crucial function of the pre-T-cell receptor (TCR) in TCR selection, TCR allelic exclusion and versus lineage commitment. Immunol. Rev. 165:111.[Medline]
6. Dudley, E. C., H. T. Petrie, L. M. Shah, M. J. Owen, A. C. Hayday. 1994. T cell receptor chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1:83.[Medline]
7. Malissen, M., J. Trucy, E. Jouvin-Marche, P. A. Cazenave, R. Scollay, B. Malissen. 1992. Regulation of TCR and gene allelic exclusion during T-cell development. Immunol. Today 13:315.[Medline]
8. Padovan, E., G. Casorati, P. Dellabona, S. Meyer, M. Brockhaus, A. Lanzavecchia. 1993. Expression of two T cell receptor chains: dual receptor T cells. Science 262:422.[Abstract/Free Full Text]
9. Koop, B. F., R. K. Wilson, K. Wang, B. Vernooij, D. Zallwer, C. L. Kuo, D. Seto, M. Toda, L. Hood. 1992. Organization, structure, and function of 95 kb of DNA spanning the murine T-cell receptor C/C region. Genomics 13:1209.[Medline]
10. Marolleau, J. P., J. D. Fondell, M. Malissen, J. Trucy, E. Barbier, K. B. Marcu, P. A. Cazenave, D. Primi. 1988. The joining of germ-line V to J genes replaces the preexisting V-J complexes in a T cell receptor , positive T cell line. Cell 55:291.[Medline]
11. Fondell, J. D., J. P. Marolleau, D. Primi, K. B. Marcu. 1990. On the mechanism of non-allelically excluded V-J T cell receptor secondary rearrangements in a murine T cell lymphoma. J. Immunol. 144:1094.[Abstract]
12. Petrie, H. T., F. Livak, D. G. Schatz, A. Strasser, I. N. Crispe, K. Shortman. 1993. Multiple rearrangements in T cell receptor chain genes maximize the production of useful thymocytes. J. Exp. Med. 178:615.[Abstract/Free Full Text]
13. Wang, F., C. Y. Huang, O. Kanagawa. 1998. Rapid deletion of rearranged T cell antigen receptor (TCR) V-J segment by secondary rearrangement in the thymus: role of continuous rearrangement of TCR chain gene and positive selection in the T cell repertoire formation. Proc. Natl. Acad. Sci. USA 95:11834.[Abstract/Free Full Text]
14. Fink, P. J., M. J. Bevan. 1995. Positive selection of thymocytes. Adv. Immunol. 59:99.[Medline]
15. Roth, M. E., P. O. Holman, D. M. Kranz. 1991. Nonrandom use of J gene segments: influence of V and J gene location. J. Immunol. 147:1075.[Abstract]
16. Letourneur, F., B. Malissen. 1989. Derivation of a T cell hybridoma variant deprived of functional T cell receptor and chain transcripts reveals a nonfunctional -mRNA of BW5147 origin. Eur. J. Immunol. 19:2269.[Medline]
17. Kanagawa, O., H. Nakauchi, R. P. Sekaly, K. Maeda, Y. Takagaki. 1990. Expression and function of the transfected CD8 chain in murine T cell hybridomas. Int. Immunol. 2:957.[Abstract/Free Full Text]
18. Gahery-Segard, H., E. Jouvin-Marche, A. Six, C. Gris-Liebe, M. Malissen, B. Malissen, P. A. Cazenave, P. N. Marche. 1996. Germline genomic structure of the B10.A mouse Tcra-V2 gene subfamily. Immunogenetics 44:298.[Medline]
19. Seto, D., B. F. Koop, P. Deshpande, S. Howard, J. Seto, E. Wilk, K. Wang, L. Hood. 1994. Organization, sequence, and function of 34.5 kb of genomic DNA encompassing several murine T-cell receptor / variable gene segments. Genomics 20:258.[Medline]
20. Marche, P. N., A. Six, H. Gahery, C. Gris-Liebe, P. A. Cazenave, E. Jouvin-Marche. 1993. T cell receptor V gene segment with alternate splicing in the junctional region. J. Immunol. 151:5319.[Abstract]
21. Arden, B., S. P. Clark, D. Kabelitz, T. W. Mak. 1995. Mouse T-cell receptor variable gene segment families. Immunogenetics 42:501.[Medline]
22. Thompson, S. D., J. Pelkonen, J. L. Hurwitz. 1990. First T cell receptor gene rearrangements during T cell ontogeny skew to the 5' region of the J locus. J. Immunol. 145:2347.[Abstract]
23. Rytkonen, M., J. L. Hurwitz, K. Tolonen, J. Pelkonen. 1994. Evidence for recombinatorial hot spots at the T cell receptor J locus. Eur. J. Immunol. 24:107.[Medline]
24. Rytkonen, M. A., J. L. Hurwitz, S. D. Thompson, J. Pelkonen. 1996. Restricted onset of T cell receptor gene rearrangement in fetal and neonatal thymocytes. Eur. J. Immunol. 26:1892.[Medline]
25. Jouvin-Marche, E., I. Hue, P. N. Marche, C. Liebe-Gris, J. P. Marolleau, B. Malissen, P. A. Cazenave, M. Malissen. 1990. Genomic organization of the mouse T cell receptor V family. EMBO J. 9:2141.[Medline]
26. Davis, M. M., P. J. Bjorkman. 1988. T-cell antigen receptor genes and T-cell recognition. [Published erratum appears in 1988 Nature 335:744.]. Nature 334:395.[Medline]
27. Janeway, C., P. Travers. 1996. Immunobiology: The Immune System in Health and Disease Garland Publishing, New York.
28. Huesmann, M., B. Scott, P. Kisielow, H. von Boehmer. 1991. Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell 66:533.[Medline]
29. Brandle, D., C. Muller, T. Rulicke, H. Hengartner, H. Pircher. 1992. Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc. Natl. Acad. Sci. USA 89:9529.[Abstract/Free Full Text]
30. Petrie, H. T., F. Livak, D. Burtrum, S. Mazel. 1995. T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182:121.[Abstract/Free Full Text]
31. Wang, K., C. L. Kuo, K. C. Cheng, M. K. Lee, B. Paeper, B. F. Koop, T. J. Yoo, L. Hood. 1994. Structural analysis of the mouse T-cell receptor Tcra V2 subfamily. Immunogenetics 40:116.[Medline]
32. Jouvin-Marche, E., C. Aude-Garcia, S. Candeias, E. Borel, S. Hachemi-Rachedi, H. Gahery-Segard, P. A. Cazenave, P. N. Marche. 1998. Differential chronology of TCRADV2 gene use by and chains of the mouse TCR. Eur. J. Immunol. 28:818.[Medline]

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