Dominant TCR Vα  usage by virus and tumor-reactive T cells with wide affinity ranges for their specific antigens

Trautmann, Lydie; Labarrière, Nathalie; Jotereau, Francine; Karanikas, Vaios; Gervois, Nadine; Connerotte, Thierry; Coulie, Pierre G.; Bonneville, Marc

doi:10.1002/1521-4141(200211)32:11<3181::aid-immu3181>3.0.co;2-2

Cited by 58 publications

(61 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TCR analysis of these clones reveals the recurrent usage of the Va12.1 chain, combined with diverse CDR3a and CDRb sequences. This dominant usage of a particular Va chain that has been previously described for the Melan-A-specific repertoire [16,17], underlines the prevalent role of the TCR-a chain in the selection of the preimmune repertoire specific for the MELOE-1 antigen and could be determinant in the generation of high frequencies of MELOE-1-specific T cells in healthy donors. Furthermore, among the amino acid residues formed by nontemplate added nucleotides in the CDR3a, 11 clonotypes shared two identical amino acid residues (GP), at positions 5 and 6 after the beginning of the CDR3 sequence, suggesting constraints on both CDR1, CDR2 and CDR3a chains for the generation of MELOE-1-specific repertoire.…”

supporting

confidence: 64%

“…Interactions between peptide-MHC complexes (pMHC) and residues at conserved positions of the CDRa loops suggest a dominant role of the Va domain in the orientation of the TCR/pMHC complex [18,19]. The dominant contribution of the CDR1 and 2 of the TCRa chain could explain the reported high frequency of Melan-A-reactive T cells in the naïve repertoire of healthy donors [16,17].To document the relevance of MELOE-1-specific T cells for use in immunotherapy, we investigated the frequency, differentiation status, TCR features and tumor reactivity of MELOE-1-specific T cells present in the periphery of HLA-A2 1 healthy donors and melanoma patients, and in melanoma TIL. …”

mentioning

confidence: 99%

“…Again, with the exception of Melan-A-specific T cells, which are found at high frequencies (up to 1 in 1 Â 10 3 CD8 1 lymphocytes) in the blood of HLA-A2 1 healthy donors and melanoma patients [12][13][14], the frequencies of other antigenspecific T cells are much lower (in the range of 1 in 1 Â 10 7 for MAGE-A3-specific T cells in healthy donors [15]). Such a high frequency of Melan-A-specific T cells in healthy donors and melanoma patients has been associated with a dominant TCR Va usage by Melan-A-specific T cells [16,17]. Indeed, the CDR1 and CDR2 of the TCRa and b chains are positioned at N and C termini of the peptide, respectively, and interact with both the peptide and MHC helices.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2010

Self Cite

View full text Add to dashboard Cite

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...

show abstract

supporting

confidence: 64%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…To identify additional sequence constraints that could predict the functional avidity of Ag recognition of A2/melan-A multimer ϩ CD8 ϩ T cells we compared TCR sequences from A2/melan-A multimer ϩ clones described in this study and recently analyzed TCR sequences of melan-A-specific CTL clones from melanoma patients (23). Within defined V␣-J␣ rearrangements, we found some CDR3␣ sequences (Table III) that were either identical (public sequences) or highly homologous among clones derived from different donors, as previously reported for high affinity T cells selected by chronic exposure to Ag (35,36).…”

Section: Resultsmentioning

confidence: 99%

“…Frequent usage of selected V␣ (i.e., V␣ 2.1) and V␤ (i.e., V␤ 14) regions, however, has also been reported (19,21,22). A more recent survey of TCR V␣-and V␤-chain usage by a large panel of melan-A-specific T cells derived from tumor-infiltrating and peripheral blood lymphocytes of melanoma patients has underlined the frequent usage (70%) of V␣ 2.1 (23). Whether this V␣ restriction results from narrowing of the TCR repertoire by affinity focusing during Ag-driven immune responses or reflects instead a structural constraint already present in the preimmune TCR repertoire, however, has remained unexplored.…”

Section: T Cells Play a Pivotal Role In The Adaptive Immune Responsesmentioning

confidence: 99%

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

Dietrich

Gal

Dutoit

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR α- and β-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more Vα- than Vβ-restricted usage. Whether Vα usage is narrowed during immune responses to Ag or if, on the contrary, restricted Vα usage is already defined at the early stages of TCR repertoire selection, however, has remained unexplored. Here, we analyzed V and CDR3 TCR regions of single circulating naive T cells specifically detected ex vivo and isolated with HLA-A2/melan-A peptide multimers. Similarly to what was previously observed for melan-A-specific Ag-experienced T cells, we found a relatively wide Vβ usage, but a preferential Vα 2.1 usage. Restricted Vα 2.1 usage was also found among single CD8+ A2/melan-A multimer+ thymocytes, indicating that Vα-restricted selection takes place in the thymus. Vα 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected Vα-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to Vα 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.

show abstract

Virus infection expands a biased subset of T cells that bind tetrameric class I peptide complexes

et al. 2003

View full text Add to dashboard Cite

We have used a TCR g -chain transgenic mouse to examine the relationship between the ability of a T cell to bind soluble class I-peptide complexes and its response to antigenic stimulation in vivo. T cells from gBT-I.3 g TCR g -chain transgenic mice preferentially carried TCR § -chains bearing the same V § 2 V region as found in the parent receptor specific for an immunodominant HSV-1 gB-peptide. Furthermore, CD8 + T cells from these mice bound K bgB tetrameric complexes with relatively high frequency, and most of these cells contained a V § 2 TCR § -chain. Detailed sequence analysis of the tetramer-binding peripheral T cells showed that this was a heterogenous population expressing TCR with only partial sequence similarity to the parent receptor, which took the form of preferential inclusion of the parental J § 16 element. Infection with HSV-1, however, selected a subset of tetramer-positive T cells. This was based on the emergence of a co-dominant J § usage and selection of a restricted CDR3 § length. Therefore, the ability to bind soluble MHC-peptide complexes does not always correlate with the ability of a T cell to respond to its cognate antigen after in vivo stimulation.

show abstract

Dominant TCR Vα usage by virus and tumor-reactive T cells with wide affinity ranges for their specific antigens

Cited by 58 publications

References 40 publications

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

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

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

Virus infection expands a biased subset of T cells that bind tetrameric class I peptide complexes

Contact Info

Product

Resources

About