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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.

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Dynamic Aspects of TCRα Gene Recombination: Qualitative and Quantitative Assessments of the TCRα Chain Repertoire in Man and Mouse

,* , and .

* Corresponding Author: Evelyne Jouvin-Marche—Université Joseph Fourier-Grenoble I, Faculté de Médecine, Institut d'Oncologie/Developpement Albert Bonniot et Institut Français du Sang, UMR-S823, Grenoble, France. Email: f.rid-srnc@ehcram.enyleve

V(D)J Recombination, edited by Pierre Ferrier.
©2009 Landes Bioscience and Springer Science+Business Media.
Read this chapter in the Madame Curie Bioscience Database here.

Most T-lymphocytes express a highly specific antigen receptor (TCR) on their cell surface, consisting of a clonotypic αβ-heterodimer. Both α- and β chains are products of somatic rearrangements of V, (D) and J gene segments encoded on the respective loci. The qualitative, quantitative and dynamic aspects of the TCRα chain repertoire of humans and mice have been difficult to estimate, mainly due to locus complexity. Analyses of the T-cell repertoire were first performed at the transcriptional level using classical cloning and sequencing strategies and then later at the genomic level using sensitive multiplex PCR assays that allow surveying the global rearrangement of the TCRAD locus. These all converge and support the conclusion that the V-J recombination pattern in both human and mouse thymus is not random but depends on the reciprocal V and J positions within the locus, thereby limiting the combinatorial diversity of the TCRα chain repertoire. The recombination profile is compatible with a sequential opening of the V region with progressive tracking along the two regions in opposite directions starting from the nearest and then moving towards the most distant V and J gene segments. In this chapter, we report new insights into the degree of human and mouse TCRα chain diversity in thymic and peripheral T-lymphocytes. Since the comparison of human and mouse V-J recombination shows a similar pattern of rearrangement, we suggest that spatial and temporal synchronization on the accessibility of V and J gene segments are general features of V-J rearrangements that are conserved throughout evolution.

Introduction

T-cell function relies on the specific recognition of foreign antigens. The majority of T-lymphocytes from humans and rodents express a clonotypic αβ TCR, which is a membrane-bound heterodimer composed of α and β chains that specifically respond to peptides derived from pathogens and bound to self-MHC molecules.1 Each chain contains a constant domain and a variable domain, the latter being responsible for MHC and peptide recognition via interaction with highly diverse complementary-determining region (CDR) loops.2 These chains are produced in differentiating lymphocytes by a series of somatic, site-specific DNA recombination reactions of multiple gene segments encoding TCR V, D and J domains.3

Lymphocytes have evolved sophisticated mechanisms for generating a diverse TCR repertoire. Multiple different copies of the V, (D) and J gene segments are each capable of contributing to a TCR antigen recognition domain and different combinations of gene segments can be used in independent rearrangement events. In addition to combinatorial diversity, variability is introduced by random removal and addition of nucleotides at the V-J or V-DJ junctions.4 This nontemplated mechanism considerably increases the repertoire. A further diversifying factor is the pairing of α and β chains5,6 to form TCR heterodimers. The potential diversity generated by random V(D)J recombination has been estimated at 1015 αβ TCRs.2 However, this number is much higher than the actual size of the peripheral T-cell compartment, estimated at around 108 in mouse and 1012 in human. Furthermore, at least some cells express the same TCR specificity.7,8 Consequently, at any given time, only a fraction of the potential repertoire (i.e., according to the random model) is achieved implying that other mechanisms must govern immune diversity.

In retrospect, the theoretical diversity of αβT-lymphocytes has been overestimated in several ways. Firstly, the T-cell repertoire has been evaluated assuming that any V gene can rearrange with any J gene in the TCRA locus. However, several sets of data on the mouse (thymus) model indicate that the number of V-J combinations is considerably lower due to a preferential association between V and J gene segments which depends on their position within the locus.9-14 Secondly, the pairing of α and β chains to form the TCR heterodimer is constrained by structural compatibility between the subunits, further limiting the repertoire.5,6 Thirdly, within the thymus, the newly generated repertoire is positively selected15,16 via interactions with self MHC molecules expressed on stromal cells, reducing the size of the generated repertoire by approximately 100-fold. Furthermore, the establishment of a peripheral T-cell repertoire depends not only on the interactions of each T-cell with their respective ligands but also on complex homeostatic mechanisms ensuring the maintenance of numbers and immune functions of lymphocyte populations.17

Clearly, the size of the available peripheral TCRαβ diversity is difficult to determine and is open to debate. While the total number of lymphocytes in the blood can be measured directly, the diversity of the lymphocyte compartment on which immunocompetence is based cannot. Despite considerable knowledge of the determinants and profile of the TCRβ chain repertoire, very little is known about human and mouse TCRα chain diversity likely due to the TCRAD locus complexity and the limited number of anti-VAD antibodies available. Thus, we have only a partial view of the entire TCRA repertoire. Molecular measurements of TCR diversity using CDR3 length analysis18 estimated about 0.5 × 106 different α chains and 106 different β chains expressed in human blood lymphocytes.19 However, this calculation was based on the analysis of TCRβ transcripts expressed in αβ T-cell clones using some V genes and with the following two assumptions: 1) the probability of rearrangement between any V gene and J gene is equal; and 2) the V families are expressed at the same level.

Evaluation of the TCR repertoire is an important measure of the immunological competence of an individual. Animal models have been more extensively studied but the degree to which these results apply to the human model has yet to be established. By making comparisons between species, we hope to learn about the general principles in operation as well as their specific origins and what this may imply about the evolution of immunity.

Complexity of Mouse and Human TCRAD Locus

The maps of both mouse and human TCRAD loci have been elucidated in the last decade and are updated by IMGT.20-22 Briefly, the human TCRAD locus spans about 1000 kb and consists of 54 V genes belonging to 41 families including 8 to 10 pseudogenes, 61 J gene segments, as well as 12 J pseudogenes, giving 49 functional Js and a unique C gene.20,23-25 Similarly, the mouse TCRAD locus is composed of 70 to more than 100 V genes depending on the haplotype, regrouped into 23 families, 60 J gene segments including 16 pseudogenes (namely J1, 3, 4, 8, 14, 19, 20, 25, 29, 36, 41, 46, 51, 55, 59 and 60) giving 44 functional Js14,20 and a unique C gene. In conclusion, the human J region contains more functional J segments able to rearrange than its mouse homologue (49 functional Js in human against 44 in mouse), providing more combinatory possibilities for the human V genes and compensating in part for the lower number of V genes compared to that in mice.

Analysis of Human and Mouse TCRA-Chain Diversity

Our previous studies on the V2 gene family of the mouse TCRAD locus indicated that rather than being stochastic, V2-J gene rearrangements depend on the respective location of the gene and occur in concentric waves.12,26 During T-cell development, J usage moves from J genes which are the closest to the V gene region to J genes located farthest from this region; similarly, V2 usage moves from V2 genes closest to the J gene region to V2 genes located at the extremity of the locus. In other words, the most proximal V2 genes target the most proximal J gene segments whereas the most distal V2 genes rearrange preferentially with the most distal Js. However, these studies were focused on V2 genes and considered them representative of all V genes. Furthermore, the analysis of V2-J gene combinations was conducted at the mRNA level. One cannot therefore exclude varied transcription efficiency between different V2 genes that may affect the distribution of the V2-J combinations. To obtain a more accurate view of the V-J diversity, we must analyze all V-J combination events at the genomic level. As already mentioned, the diversity of the mammalian TCR repertoire is generated by gene rearrangement. We therefore developed a PCR assay allowing visualization at the DNA level of several contiguous recombination events between a given V gene or V gene family and several J genes segments of the TCRAD locus. As described in Figure 1, in each PCR assay, J primers were chosen to hybridize a downstream sequence allowing amplification of four to seven different J genes. Thus, a panel of nine to eleven J primers allowed the description of the rearrangement status of all functional mouse and human J genes and provided a global visualization of rearrangement patterns (Fig. 2).

Figure 1. Schematic representation of multiplex PCR analysis of TCRA gene rearrangements.

Figure 1

Schematic representation of multiplex PCR analysis of TCRA gene rearrangements. Briefly, by using two specific primers, one upstream of a given V gene and another downstream of a given J gene, the PCR will amplify all rearrangements involving both of (more...)

Figure 2. Multiplex PCR assays of V-J rearrangements of the mouse and human TCRAD locus.

Figure 2

Multiplex PCR assays of V-J rearrangements of the mouse and human TCRAD locus. Genomic DNA was extracted from thymus and amplified using primers situated downstream of different J genes and spread over the J gene region, together with a primer specific (more...)

Genomic multiplex PCR analysis of mouse TCRα chain diversity confirms previous data at the rearrangement level, in that V-J rearrangements are not random but depend on the V and J positions within the locus. For example, in the mouse thymus, V families located closest to the C coding region, such as V19 and V20, rearrange predominantly with the most proximal Js ( J60 to J48) and rarely with the J segments located in the mid-section or the distal part of the J region (shown in Fig. 3). Reciprocally, V1 and V2 situated in the most distal part of the V gene region preferentially rearrange with the J segments found in the mid-section or distal parts of the J region but not with the Js found more proximally. Thus, the TCRAD locus is accessible from the 3′ end of the V region and from the 5′ end of the J region and consequently the proximal V and J genes are the first gene segments accessible for recombination followed later on by more distal V and J segments. In addition, we reported that depending on its locus position, each V gene differentially rearranged with a set of contiguous Js with a gaussian-like distribution.14 For instance, the real time PCR quantification of V1 and V21 rearrangements revealed that the proximal V21 gene used a small set of J genes, less than 10, but with a 6 fold higher frequency than distal V genes which used a larger panel of J genes (more than 32). These preferential associations between V and J genes were observed with different V genes located at different positions in the TCRAD locus, suggesting that each V gene targeted particular sets of J segments.

Figure 3. V-J rearrangement depends on V and J localization within the TRAD locus.

Figure 3

V-J rearrangement depends on V and J localization within the TRAD locus. V-J specifi c rearrangements were analyzed by multiplex PCR on DNA extracted from total thymus of a 6 day-old human (upper panel) and from total thymus of a 6 week old Balb/c mouse (more...)

A similar multiplex PCR experimental approach has been used to characterize the α chain repertoire in human thymi. By focusing the analysis on single member families to correlate the position of each V gene with its rearrangement pattern (Fig. 3, top panels), it can be observed that the two V genes most distant from the J region (V1, V2, located at -925 and -835 kb from the C gene, respectively) rearrange with the central and 3′ end of the J region, whereas the three J-proximal V genes, namely V38, V40 and V41, located between -267 to -227 kb with respect to the C gene, mainly rearrange with the most proximal Js. Finally, the members of the multigenic V8 family located in the middle part of the locus, including members located at -701, -653 and -569 kb respectively from the C region, rearrange to approximately the same extent with all the J segments throughout the locus. Taken together, the data show preferential distribution of recombination of particular V families to certain J gene segments depending on their localization within the locus. These findings are consistent with the model of synchronized waves of accessibility moving in a concentric manner across both V and J gene regions. These waves of rearrangement move from J genes located proximal to the V region towards J genes located closer to the C gene and from V genes located proximal to J region towards more distally located V genes, supporting the bi-directional and coordinated model postulated in the mouse.13,14 In conclusion, the comparison of human and mouse TCRA V-J recombination in the thymus shows a similar pattern of rearrangement suggesting that this mechanistic regulation of the process is conserved throughout evolution.

Comparison between the Frequencies of Rearrangements in Thymus and Peripheral T-lymphocytes

In order to gain further insight into the frequencies of V-J combinations, we set up a precise quantification of rearrangements by real-time genomic quantitative PCR (qPCR). Particular V and J genes were selected as representative of several locations in the TCRAD locus and qPCR was carried out with DNA from thymi (Fig. 4A) and from peripheral blood lymphocytes (PBLs) (Fig. 4B). While the patterns of V-J combinations appear similar among individuals and follow the general rules, some discrete differences in recombination frequencies are detected when comparing the patterns obtained in the thymus and peripheral T-lymphocyte DNA. Several observations emerge from these detailed analyses. Firstly, some V-J combinations (i.e., V1-J56, V1-J53, V40-J10 and V41-J10) are not detectable either in the thymus or the PBL, presumably because they are very infrequent. This result confirms the combinatorial pattern described in Figure 3, dependent on the reciprocal position of the V and J genes within the locus. Secondly, some combinations are favored in the periphery with respect to others (for instance V1-J33 can be found at a high frequency in all samples tested). Thirdly, some rearrangements are quantitatively less abundant in the periphery with respect to the thymus. In particular, proximal V-J rearrangements, like V40-J56 or V40-J53, are weakly found (at 6 to 8 cycles of qPCR) in the periphery compared to their high frequency in thymus samples. Several possibilities may account for these differences, including: (1) variation in the number of T-cells between thymus and PBL samples; (2) the contribution of rearrangements occuring on excision circles (these may be more frequently amplified in thymus than in peripheral T-cells in which excision circles have been diluted); (3) the occurrence of secondary rearrangements in the thymus or receptor revision events in the periphery which would replace the most-proximal and accessible V-J rearrangements by joining between more distal V and J genes;27 (4) positive and negative selection events.28 Finally, the expansion/contraction of specific rearrangements (i.e., V40-J41, V1-J41, V1-J10) can be identified in certain individuals. Taken together, this analysis demonstrates that, while the recombination pattern is quantitatively similar in thymus samples of several individuals, more heterogeneity of V-J combination is observed in the peripheral T-cell. These observations may indicate the sharing amongst individuals of thymic selection events with similar impact on V-J combination, whereas a divergence amongst individuals in the periphery regarding some V-J combinations could reflect expansions of particular clonotypes induced by immune responses or homeostatic maintenance forces.

Figure 4. Relative abundance of V-J specific rearrangements among healthy individuals as determined by quantitative genomic PCR analysis.

Figure 4

Relative abundance of V-J specific rearrangements among healthy individuals as determined by quantitative genomic PCR analysis. The investigated rearrangements involved V1, 40, 41 and J56, 53, 41, 33, 10 of the human TCRAD locus. The results are expressed (more...)

The Size of the Mouse and Human TCRα Repertoire

Dependent on the locus position together with the differential expression of V families, preferential V-J recombination leads to a restriction of the potential combinatorial TCR α chain repertoire. By analyzing heterogeneity in CDR3 sequences, the diversity of the human α chain repertoire was estimated at around 0.5 × 106 chains in the blood.19 However, in this calculation, all the human TCRA V-J combinations were considered as equally likely. The theoretical number of combinations if all 54 V genes could rearrange to each of the 61 J gene segments within the locus is 3294. However, only 46 human V genes and 49 J segments are available for rearrangement. Taking into account (i) that the recombination of proximal V genes including V1.1 to V7 is restricted to the closest half of the J region corresponding to approximately 32 Js; (ii) that the central V genes rearrange with about 45 J gene segments; and (iii) that the distal V genes, (i.e., V31 to V41) do not rearrange with the first 9 Js giving 9 functional V genes rearranging with 40 Js, then the number of possible V-J combinations is less than 2000 (8V × 32 J + 29V × 45 + 9V × 40 J). This suggests that the actual number of combinations corresponds to less than 60% of the estimated 0.5 × 106 total combinatorial possibilities, i.e., 0.3 × 106 TCRα chains. This value is also likely overestimated as it does not take into account the different frequencies of utilization of V and J gene segments within the locus. Concerning mouse, the number of different α chains have been estimated as around 1.2 × 104 in the C57Bl/6 or B10 TCRAD haplotype.4 It is worth noting that the number of V genes varies from 1 to 3 fold among different haplotypes, for instance the C57Bl/6 haplotype possesses 1/3 less V genes compared to the Balb/c haplotype12,29 leading to an estimated 0.8 × 104 TCRα chains in the Balb/c haplotype. In addition, multiple rounds of V gene duplications mean that most V families contain between 2 and 10 members, in some cases perhaps differing by only one to three punctual mutations scattered through the V genes.30 This prevents a precise determination of the number of J segments used by V genes. In the Balb/c TCRA haplotype, (i) the most proximal V genes (V21 to V23) are found rearranged to less than 10 J genes (those between J60 to J48), (ii) the middle V genes use a panel of about 35 Js and finally (iii) the distal V genes (V1 to V3.1) use a panel of less than 30 J segments. Using this information, we estimated a reduction of around 30% in the number of V-J combinations in Balb/c mice compared to the theoritical number of combinations (ref.14 and our unpublished results) yielding an estimated 0.6 × 104 different α chains. Taken together, these findings indicate that whilst remaining large enough to maintain a high functional diversity, limitations of combinatorial diversity reduce the size of the available human and mouse TCR α chain repertoires.

Conclusion

The fact that V and J gene segments combine preferentially according to their position in the TCRA locus suggests a control of rearrangements depending mostly on the strict regulation of chromatin accessibility in both the V and J gene regions (Fig. 5). Cis-acting elements, particularly enhancers and promoters, have been proposed as being involved in chromatin remodelling.31,32 In the murine TCRA locus, accessibility of the J region is controlled by the Eα enhancer located 3′ of the C coding region.33 In addition, two promoters contribute to the control of Jα rearrangements, namely the T early α (TEA) at the 5′ end of the J region and a second promoter located 15 kb downstream of TEA before the J49 coding region. Both promoters can be activated by Eα.34,35 The TEA promoter has been shown to spatially regulate J gene utilization36 and drive noncoding transcription to positively and negatively instruct the activity of downstream J promoters.37 Interestingly, TEA transcription has been proposed to target V rearrangements to the 5′ end of the J region and consequently determines the rearrangement profile of this region by promoting the activation of proximal J promoters ( J58 to J56) while repressing that of more distal J promoters (see chapter by Abarrategui and Krangel). These recent data on the role of TEA transcription on J gene accessibility support the recombination profiles discussed in this report. Whilst we are beginning to gain a better understanding of the mechanisms contributing to the use of J segments, the process of V gene accessibility to rearrangement and the control of their uses remain to be elucidated.

Figure 5. Schematic representation of the V-J combinations in TCRA rearrangements.

Figure 5

Schematic representation of the V-J combinations in TCRA rearrangements. V and J genes were respectively categorized according to their respective relative locations in the TCRA locus as distal (white dashed boxes), middle (grey boxes) and proximal (black (more...)

The evaluation of the TCR repertoire is an important measure of the immune competence of an individual. It is assumed that the larger the number of distinct immune T-cells, the more efficient the protection against infectious diseases. Consequently, the size and diversity of the available repertoire are crucial in shaping the immune response to a given antigen. Our studies strongly suggest that although it remains large enough to maintain a high functional diversity, the TCR repertoire of human and mouse α chains is smaller than that predicted by the random rearrangement model. Detailed knowledge about the extent and diversity of the TCR repertoire used in specific immune responses will facilitate the ability to understand the role of the TCR genes in normal and disease states. Whereas clonal populations are hallmarks of malignancy, clonal or oligoclonal populations of T- and B-lymphocytes may also arise in nonmalignant conditions, including normal individuals (responses against some pathogens such as HIV and EBV), elderly patients and patients suffering from autoimmunity or immunodeficiency. Our straightforward experimental approach enables a qualitative and quantitative description of the overall TCRα chain diversity in humans and offers a unique opportunity to characterize and track the repertoire for each individual in healthy and diseased states.

Acknowledgements

The authors wish to thank J Conway, MA Thelu and HL Dougier for their helpful discussions and comments. This work was supported by institutional grants from the Institut National de la Santé et de la Recherche Médicale and from the Commissariat à l'Energie Atomique and partly by specific grants from the Agence Nationale pour la Recherche sur le SIDA et les Hépatites and the Ligue Contre le Cancer. P Fuschiotti was recipient of a fellowship from the Centre National de la Recherche Scientifique.

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