The tight interallelic positional coincidence that distinguishes T-cell receptor Jalpha usage does not result from homologous chromosomal pairing during ValphaJalpha rearrangement

Davodeau, François; Difilippantonio, Michael J.; Roldán, Esther; Casanova, Jean‐Laurent; Couedel, Chrystelle; Morcet, Jean‐François; Merkenschlager, Matthias; Nussenzweig, André; Bonneville, Marc; Malissen, Bernard

doi:10.1093/emboj/20.17.4717

Cited by 44 publications

(43 citation statements)

References 35 publications

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“…T cell lines and T cell clones were phenotyped by indirect immunofluorescence using mAb against TCR V␤ regions (30,31). Stainings with NLV/A2 tetramer were performed by incubating cells for 1 h at room temperature with PE-labeled pMHC tetramer at 20 g/ml in PBS-BSA 0.1%.…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses

Trautmann

Rimbert²,

Echasserieau

et al. 2005

The Journal of Immunology

214

243

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Assessment of clonal diversity of T cell responses against human CMV (HCMV), a major cause of morbidity in immunodepressed patients, provides important insights into the molecular basis of T cell immunodominance, and has also clinical implications for the immunomonitoring and immunotherapy of HCMV infections. We performed an in-depth molecular and functional characterization of CD8 T cells directed against an immunodominant HLA-A2-restricted epitope derived from HCMV protein pp65 (NLV/A2) in steady state and pathological situations associated with HCMV reactivation. NLV/A2-specific T cells in healthy HCMV-seropositive donors showed limited clonal diversity and usage of a restricted set of TCR Vβ regions. Although TCRβ-chain junctional sequences were highly diverse, a large fraction of NLV/A2-specific T cells derived from distinct individuals showed several recurrent (so-called “public”) TCR features associated in some cases with full conservation of the TCRα chain junctional region. A dramatic clonal focusing of NLV/A2-specific T cells was observed in situations of HCMV reactivation and/or chronic inflammation, which resulted in selection of a single clonotype displaying similar public TCR features in several patients. In most instances the NLV/A2-specific dominant clonotypes showed higher affinity for their Ag than subdominant ones, thus suggesting that TCR affinity/avidity is the primary driving force underlying repertoire focusing along chronic antigenic stimulation.

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Section: Flow Cytometric Analysismentioning

confidence: 99%

Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses

Trautmann

Rimbert²,

Echasserieau

et al. 2005

The Journal of Immunology

214

243

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“…Reverse transcriptions, PCR amplifications and sequencing were performed as described [16,34]. We have followed throughout the manuscript the TCR nomenclature established by Arden et al [35].…”

Section: Sequence Analysis Of Tcr Transcriptsmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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“…Deletion of the TEA element reveals that beyond the global control of Enh § over the entire region, a particular window of J § segments (the 9 most 5´J § in a total of 61) is under the direct control of TEA during the V-J § rearrangements [15]. Furthermore, in the J § cluster, both alleles of the locus are rearranged with a tight interallelic coincidence that relies on the presence of TEA [16,17]. Such phenomenons led us to propose that TEA confers a hyperaccessibility to the 5´end of the J § cluster on both alleles, thus targeting the first waves of V § J § rearrangements and establishing the interallelic coincidence.…”

Section: Introductionmentioning

confidence: 99%

TEA regulates local TCR‐Jα accessibility through histone acetylation

2003

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Enhancer § -dependent histone acetylation has been proposed as a molecular mechanism underlying the control of accessibility of recombination signal sequences along the TCR § locus. Here we show that chromatin acetylation along the first J § segments is under the dependence of the T early § element (TEA), located upstream of TCRJ § locus. The targeted deletion of TEA leads to an absence of histones H3 and H4 tail acetylation, while maintaining histone acetylation in the region spanning downstream J § segments. During thymocyte maturation, TEA-dependent histone acetylation appears at immature single-positive stage, known to represent the stage of V § J § initiation. TEA-dependent histone acetylation of the most upstream J § segments leads to enhanced DNA accessibility thus optimizing TCRJ § usage and increasing Ag receptor diversity potential.

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The tight interallelic positional coincidence that distinguishes T-cell receptor Jalpha usage does not result from homologous chromosomal pairing during ValphaJalpha rearrangement

Cited by 44 publications

References 35 publications

Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses

Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

TEA regulates local TCR‐Jα accessibility through histone acetylation

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