Identification of a public CDR3 motif and a biased utilization of T-cell receptor V beta and J beta chains in HLA-A2/Melan-A-specific T-cell clonotypes of melanoma patients

Serana, Federico; Sottini, Alessandra; Caimi, Luigi; Palermo, Belinda; Natali, Pier Giorgio; Nisticò, Paola

doi:10.1186/1479-5876-7-21

Cited by 31 publications

(40 citation statements)

References 57 publications

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“…These TRAV-TRBV biases are specific to the Melan-A Ag, because such repertoire distribution was not observed in the T cell responses induced in other well-described tumor and viral systems (37, 39 -42). Similarly, the dominant usage of the TRBJ1-5 (by 19.6% of all sequences) is also a characteristic signature of the Melan-A response (35). Finally, we describe for the first time that the TRBV repertoire after vaccination with the natural peptide is more diverse but yet overlaps the repertoire selected by vaccination with the analog peptide.…”

Section: Discussionmentioning

confidence: 78%

“…The "GLG" motif has been recently described as a public sequence (35). Analysis of the amino acids contributing to this central motif showed subtle differences in the CDR3 from the natural and the analog cohort of vaccinated patients (Fig.…”

Section: Trbv Sequence Alignment Reveals Conservation Of the Cdr3␤ Ammentioning

confidence: 99%

“…Recently, Serana and colleagues (35) have compiled 210 TRBV single sequences from the literature and pointed out, beside a high heterogeneity in the TCR␤ repertoire, the preferential usage of TRBV4, 6, 20, 27, and 28, and of TRBJ1-5, 2-1, and 2-7 in HLA-A2/Melan-A-restricted CD8 T cells from melanoma patients. In this study, we show that TRBV4, 6, 19, 27, and 28 segments were the most representative of the Melan-A-specific responses induced in all eight patients, and altogether were used by a median of 61.8 and 75.9% of the clones in the natural and analog cohorts respectively ( Fig.…”

Section: Trbv Repertoire Derived From Natural Peptide Vaccinated Patimentioning

confidence: 99%

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Fine Structural Variations of αβTCRs Selected by Vaccination with Natural versus Altered Self-Antigen in Melanoma Patients

Wieckowski

Baumgaertner

Corthésy

et al. 2009

The Journal of Immunology

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Immunotherapy of cancer is often performed with altered “analog” peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26–35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3α composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such “public” motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with “private” CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.

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Section: Discussionmentioning

confidence: 78%

Section: Trbv Sequence Alignment Reveals Conservation Of the Cdr3␤ Ammentioning

confidence: 99%

Section: Trbv Repertoire Derived From Natural Peptide Vaccinated Patimentioning

confidence: 99%

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Fine Structural Variations of αβTCRs Selected by Vaccination with Natural versus Altered Self-Antigen in Melanoma Patients

Wieckowski

Baumgaertner

Corthésy

et al. 2009

The Journal of Immunology

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show abstract

“…Thus, regardless of the priming peptide, we detected a clear bias toward TRBV4-1, TRBV6-2/6-3, TRBV6-5, TRBV27, and TRBV28 gene usage in the responding repertoires. Furthermore, glycine was commonly used within the CDR3 cores, and the previously described GXG motif was observed in several of the responding clonotypes (52,54). However, despite these preferences, the majority of clonotypes were nonoverlapping between the two repertoires (Fig.…”

Section: Discussionmentioning

confidence: 99%

Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition

Cole

Edwards

Wynn

et al. 2010

The Journal of Immunology

118

167

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Improving T-cell antigens by altering MHC anchor residues is a common strategy used to enhance peptide vaccines but there has been little assessment of how such modifications affect TCR binding and T-cell recognition. Here, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T-cells that exhibit a strong preference for either type of antigen. Furthermore, we show that anchor-modified heteroclitic peptides prime T-cells with different TCRs compared to those primed with natural antigen. Thus, vaccination with heteroclitic peptides may elicit T-cells that exhibit suboptimal recognition of the intended natural antigen and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.

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“…Since then, many observations of public TCRs in a variety of infectious diseases (Table 1), including human cytomegalovirus [3][4], parvovirus B19 [5], Clostridium tetani [6], Herpes simplex virus [7], and HIV [8][9][10], have been reported. The involvement of public TCRs in malignancy was also observed in tumorassociated antigen-specific T cells from melanoma [11][12][13][14][15], synovial sarcoma and prostate cancer [16][17] (Table 1). Public TCRs also occurred in autoimmune diseases such as multiple sclerosis [18], reactive arthritis [9], aplastic anemia [20], psoriasis vulgaris [21], systemic sclerosis [22], sarcoidosis [23], and rheumatoid arthritis [24] (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Determinants of public T cell responses

et al. 2012

Cell Res

115

112

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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Identification of a public CDR3 motif and a biased utilization of T-cell receptor V beta and J beta chains in HLA-A2/Melan-A-specific T-cell clonotypes of melanoma patients

Cited by 31 publications

References 57 publications

Fine Structural Variations of αβTCRs Selected by Vaccination with Natural versus Altered Self-Antigen in Melanoma Patients

Fine Structural Variations of αβTCRs Selected by Vaccination with Natural versus Altered Self-Antigen in Melanoma Patients

Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition

Determinants of public T cell responses

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