How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides?

Mazza, Catherine; Auphan-Anezin, Nathalie; Grégoire, Claude; Guimezanes, Annick; Kellenberger, Christine; Roussel, Alain; Kearney, Alice; Merwe, P. Anton van der; Schmitt-Verhulst, Anne-Marie; Malissen, Bernard

doi:10.1038/sj.emboj.7601605

Cited by 95 publications

(104 citation statements)

References 45 publications

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“…The concept that cancer cells can be targeted by T cells recognizing self-peptides presented by foreign HLA was first described by Stauss and coworkers (15)(16)(17). Although these and other studies have shown that certain peptides can be specifically recognized when presented on allogeneic HLA (8,9,12,(18)(19)(20)(21)(22)(23), it seemed possible that they represented exceptions, because there is also evidence that allorestricted cells are more promiscuous with regard to peptide recognition (9,18,(24)(25)(26)(27)(28). However, when assessing reactivity to a large number of epitopes at the single-cell level, we did not find evidence suggesting that peptide recognition on foreign HLA generally has a low specificity.…”

Section: Discussionmentioning

confidence: 99%

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Kumari

Wälchli

Fallang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2-negative donors as tools to detect HLA-A2-bound peptides from two leukemiaassociated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide-HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide-and HLA-specific and responded strongly to HLA-A2-positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T-cell repertoires.C ytotoxic T cells (CTLs) selectively kill target cells that express defined peptides in complex with MHC class I molecules on the cell surface. Most tumor-associated antigens (TAA) are wild-type self-proteins, and T cells that recognize peptides from these antigens with high affinity are deleted during thymic development. Thus, the utility of T cells for detection of self-peptides presented on self-HLA is limited by tolerance. This may be one reason why the number of epitopes identified from TAA after 2 decades of intense research amounts to less than 600 (1). The ability to rapidly identify new CTL epitopes would likely facilitate the development of effective immunotherapeutic strategies against cancer.MHC molecules can be isolated from cells and the associated peptides eluted for identification by MS. Ultimately, this approach may provide a description of the entire MHC-bound peptide repertoire: the immunopeptidome (2, 3). This is, however, a daunting task, and it is unclear whether current MS-based protocols already provide the required sensitivity. Indeed, although 100,000-750,000 peptide-MHC class I complexes are expressed for each allelic product on the cell surface (for HLA-A and HLA-B loci) (3, 4), the largest HLA ligandome identified to date contains 14,065 peptides (5). In contrast, the predicted number of different HLA class I ligands would be 352,000 using the well-renowned computer algorithm NetMHCpan, considering that on average, 4.4% of all nonamers bind HLA class I (6) and that a cell contains at least 8 × 10 6 distinct nonamers (7). Thus, there is a very large gap between the numb...

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Section: Discussionmentioning

confidence: 99%

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Kumari

Wälchli

Fallang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The set of tryptic peptides bound by each individual CIMS antibody was thus detected and identified using tandem-mass spectrometry. The results showed that peptides of a median length of 10 amino acids (range [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and with a median pI of 6.5 (range 3.8-12) were captured in a clone-dependent manner (Table I). Noteworthy, as illustrated for the CIMS-17 sister pair, the affinity (K D ) for an experimentally verified captured yeast peptide was found to be in the same range as that observed for the original selection peptide (Table I).…”

Section: Degenerate Peptide-binding Specificitymentioning

confidence: 93%

“…15,16 The available crystal structures of liganded and unliganded TCRs have implied that the flexibility of the TCR combining site facilitates TCR adaptation to rather conformationally constrained MHC-peptide surfaces. [27][28][29] Based on the SH3 work, 25,26 the importance of the affinity for peptide binding promiscuity has been highlighted, and such interactions tend, as might be expected, to be of low affinity.…”

Section: Discussionmentioning

confidence: 99%

“…12 In fact, even the TCRs have been shown to exhibit promiscuous binding properties to non-overlapping peptides. [13][14][15][16] It has been argued that the individual TCR, as well as antibody combining sites, is composed of a packet of specificities randomly plucked from the repertoire, hence being poly-specific, which in turn should be dissected into two features, specificity and degeneracy. 17 Notably, recent studies based on X-ray crystallography have supported the possibility of peptide binding promiscuity, or poly-specificity (cross-reactivity) also for antibodies.…”

Section: Introductionmentioning

confidence: 99%

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Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

et al. 2012

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Protein-peptide interactions are a common occurrence and essential for numerous cellular processes, and frequently explored in broad applications within biology, medicine, and proteomics. Therefore, understanding the molecular mechanism(s) of protein-peptide recognition, specificity, and binding interactions will be essential. In this study, we report the first detailed analysis of antibody-peptide interaction characteristics, by combining large-scale experimental peptide binding data with the structural analysis of eight human recombinant antibodies and numerous peptides, targeting tryptic mammalian and eukaryote proteomes. The results consistently revealed that promiscuous peptide-binding interactions, that is, both specific and degenerate binding, were exhibited by all antibodies, and the discovery was corroborated by orthogonal data, indicating that this might be a general phenomenon for low-affinity antibodypeptide interactions. The molecular mechanism for the degenerate peptide-binding specificity appeared to be executed through the use of 2-3 semi-conserved anchor residues in the C-terminal part of the peptides, in analogue to the mechanism utilized by the major histocompatibility complex-peptide complexes. In the long-term, this knowledge will be instrumental for advancing our fundamental understanding of protein-peptide interactions, as well as for designing, generating, and applying peptide specific antibodies, or peptide-binding proteins in general, in various biotechnical and medical applications.

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“…Ref. 9). In one telling case, however, the conformation of the ␣2 helix of the human class I MHC protein HLA-A*0201 (HLA-A2) was shown to undergo a large reorganization upon binding of the A6 TCR (10).…”

mentioning

confidence: 99%

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

Hawse¹,

Gloor²,

Ayres³

et al. 2013

Journal of Biological Chemistry

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Background: Peptide modulation of MHC flexibility can affect recognition by immune receptors. Results: Different peptides alter the flexibility of the MHC protein at sites around the peptide-binding groove. Conclusion: Peptide modulation of MHC flexibility is not limited to specific peptides or isolated regions. Significance: Peptide modulation of MHC flexibility indicates an extension of antigenicity from the peptide to the MHC.

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How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides?

Cited by 95 publications

References 45 publications

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

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