V(D)J Recombinase-Mediated TCR β Locus Gene Usage and Coding Joint Processing in Peripheral T Cells during Perinatal and Pediatric Development

Murray, Janet; Messier, Terri L.; Rivers, Jami; O’Neill, J. Patrick; Walker, Vernon E.; Vacek, Pamela M.; Finette, Barry A.

doi:10.4049/jimmunol.1200382

Cited by 12 publications

(21 citation statements)

References 42 publications

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“…We have observed a progressive increase of TRB repertoire diversity and evenness during fetal development so that diversity at 22 to 26 WGA was indistinguishable from what was observed in healthy control infants. Together, our findings confirm and extend previous observations of nonrandom usage of TRAV and TRBV genes (46)(47)(48) and a slow increase in the extent of N nucleotide addition (45) and CDR-B3 length (28) during fetal development.…”

Section: Discussionsupporting

confidence: 91%

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

et al. 2015

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Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function.

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Section: Discussionsupporting

confidence: 91%

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

et al. 2015

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“…Studies by Murray et al have demonstrated genderspecific V(D)J recombinase-mediated TCRb gene usage and coding joint processing in human development that demonstrate direct effects on TCR diversity, though these studies were conducted on healthy children at a maximum age of 12.5 y. 63,64 In this study, these gender-specific differences in clonality did not occur across compartments -an observation that did occur with age-related associations, thus the strength of this gender-specific observation in NSCLC needs to be further evaluated in subsequent studies.…”

Section: E1051922-6 Volume 4 Issue 12 Oncoimmunologymentioning

confidence: 99%

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4⁺T cell receptor repertoire clonality

et al. 2015

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Keywords: deep sequencing, non-small cell lung cancer, TCR/BCR repertoire, tertiary lymphoid structure Abbreviations: ADC, adenocarcinoma; BCR, B cell receptor; CDR3, complementarity-determining region 3; DC, dendritic cell; Foll-B cell, follicular B cell; IgH, immunoglobulin heavy chain; LCC, large-cell carcinoma; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; NT, non-tumoral distant tissue; P, peripheral blood or draining lymph node; SCC, squamous cell carcinoma; TFH, follicular helper T cell; TRM, tissue resident-memory T cell; TCR, T cell receptor; TLS, tertiary lymphoid structure.T and B cell receptor (TCR and BCR, respectively) Vb or immunoglobulin heavy chain complementarity-determining region 3 sequencing allows monitoring of repertoire changes through recognition, clonal expansion, affinity maturation, and T or B cell activation in response to antigen. TCR and BCR repertoire analysis can advance understanding of antitumor immune responses in the tumor microenvironment. TCR and BCR repertoires of sorted CD4 C , CD8C or CD19 C cells in tumor, non-tumoral distant tissue (NT), and peripheral compartments (blood/draining lymph node [P]) from 47 non-small cell lung cancer (NSCLC) patients (age median D 68 y) were sequenced. The clonotype spectra were assessed among different tissues and correlated with clinical and immunological parameters. In all tissues, CD4C and CD8 C TCR repertoires had greater clonality relative to CD19 C BCR. CD4 C T cells exhibited greater clonality in NT compared to tumor (p D 0.002) and P (p < 0.001), concentrated among older patients (age > 68). Younger patients exhibited greater CD4 C T cell diversity in P compared to older patients (p D 0.05), and greater CD4 C T cell clonality in tumor relative to P (p < 0.001), with fewer shared clonotypes between tumor and P than older patients (p D 0.04). More interestingly, greater CD4C and CD8 C T cell clonality in tumor and P, respectively (both p D 0.05), correlated with high density of tumor-associated tertiary lymphoid structure (TLS) B cells, a biomarker of higher overall survival in NSCLC. Results indicate distinct adaptive immune responses in NSCLC, where peripheral T cell diversity is modulated by age, and tumor T cell clonal expansion is favored by the presence of TLSs in the tumor microenvironment.

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“…Non-templated nucleotides are inserted by terminal deoxynucleotidyl transferase (TdT), and previous studies of its activity showed that insertion of nucleotides into coding junctions is not random [49, 50, 53]. A preference for G nucleotide insertions was observed during V(D)J recombination of plasmid substrates and in vivo , thus G/C nucleotides are present in coding junctions at higher levels than A/T nucleotides [50, 53].…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we conducted an expanded frequency, clonality, and junctional processing analysis of illegitimate V(D)J deletion events at these loci during several stages of mouse development in wild-type animals. Results are discussed in the context of similar analyses of bona fide V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate events at the nonimmune HPRT1 locus found in human peripheral T cells that are not associated with T cell malignancies [49, 50]. …”

Section: Introductionmentioning

confidence: 99%

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

Champagne

Shockett

2014

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is similar for both genes and consistent with results at the TCRβ locus. Non-templated (N) nucleotide insertions appear to increase between fetal and postnatal stages for Notch1, consistent with normal terminal deoxynucleotidyl transferase (TdT) activity; however, neonatal Bcl11b junctions contain elevated levels of N insertions. Finally, contrasting with results at the HPRT1 locus, we find no obvious age or gender bias in junctional processing, and inverted repeats at recessed coding ends (Pr nucleotides) correspond mostly to single-base additions consistent with normal TdT activity.

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V(D)J Recombinase-Mediated TCR β Locus Gene Usage and Coding Joint Processing in Peripheral T Cells during Perinatal and Pediatric Development

Cited by 12 publications

References 42 publications

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4⁺T cell receptor repertoire clonality

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

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V(D)J Recombinase-Mediated TCR β Locus Gene Usage and Coding Joint Processing in Peripheral T Cells during Perinatal and Pediatric Development

Cited by 12 publications

References 42 publications

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

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A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4⁺T cell receptor repertoire clonality