Specific T cell recognition of minimally homologous peptides: Evidence for multiple endogenous Ligands

Evavold, Brian D.; Sloan-Lancastert, Joanne; Wilson, Kerry‐Jayne; Rothbard, Jonathan B.; Allen, Paul M.

doi:10.1016/1074-7613(95)90010-1

Cited by 198 publications

(121 citation statements)

References 63 publications

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“…T-cell cross-reactivity based on minimal epitope identity has been shown for both CD4 ϩ and CD8 ϩ T cells in different experimental setups. [23][24][25] These reports clearly demonstrate that peptide identity based on only 1 or 2 amino acid residues is sufficient to explain T-cell activation by nonhomologous peptides. However, the recognition of peptide analogues by mature T cells seldom leads to full activation of the T cell and in some cases peptide analogues even act as TCR antagonists or partial agonists involved in downregulation of T-cell responses.…”

Section: Ctl Killing Of Natural Targetsmentioning

confidence: 99%

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

et al. 2001

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p53 is upregulated in the majority of spontaneous tumors and the HLA class I molecule HLA-A2 is expressed by approximately 50% of the caucasians. Potentially, these facts make HLA-A2-binding p53 peptides for CTL-inducing immunotherapy applicable to a broad range of cancer patients. In our study, we investigated the CTL-inducing capacity of autologous monocyte-derived dendritic cells (DC) maturated by exposure to CD40L and pulsed with a pool of 4 wild-type, HLA-A2-binding p53 peptides, and the p53-specific CD8 ؉ CTL lines established from healthy HLA-A2-positive donors were characterized. Reactivity to p53 65-73 and p53 [187][188][189][190][191][192][193][194][195][196][197] peptides was obtained in the T-cell lines. Interestingly, cold target inhibition experiments demonstrated that the simultaneous recognition of the 2 peptides was the result of crossreactivity, which was confirmed by killing experiments at the clonal CTL level. Furthermore, 4 HLA-A2 ؉ p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wildtype p53 peptides presented by several cancer cell lines. In addition, the recognition of 2 different p53 peptides by the same CTL clone suggests a promiscuous peptide recognition by the TCR involved. Taken together, these in vitro results suggest that vaccination with autologous DC pulsed with multiple p53 epitopes may induce an effective tumor-specific CTL response in vivo with the potential to eradicate p53-upregulated spontaneously occurring tumors. © 2001 Wiley-Liss, Inc. Key words: p53; cytotoxic T-lymphocytes; HLA-A2; dendritic cellsThe cell cycle regulating protein p53 binds to DNA with coincidental nucleotide misincorporations and leads to cell cycle arrest and DNA repair. 1 The involvement of p53 at this crucial checkpoint in the cell division is probably reflected by the fact that inactivating mutations in the p53 genome are found in the majority of human cancer diseases. 2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.Recently, several clinical studies on cancer immunotherapy using different approaches to activate cytotoxic T cells in vivo [7][8][9] or ex vivo 10 recognizing individual tumor antigens have been highly successful. These results underscore the efficiency of the immune system in controlling tumor growth and emphasize the importance of characterizing CTL specific to general tumor antigens. Four studies on...

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Section: Ctl Killing Of Natural Targetsmentioning

confidence: 99%

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

et al. 2001

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“…[14][15][16][17][19][20][21][22][23][24][25] In the present study, to further analyze the TCR ligands of the PDC-E2 163-176 -reactive T cells, we investigated the response of PDC-E2 163-176 -reactive cloned T-cell lines to a panel of single amino acid-substituted peptides derived from the PDC-E2 163-176 peptide. We found that each T-cell clone had a different pattern of reactivity to a panel of these analogue peptides, indicating the presence of a variety of T-cell repertoire for a single TCR ligand such as the PDC-E2 163-176 peptide/HLA DR53 complex.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular mimicry between foreign and self-antigens have been implicated as a possible mechanism for the activation of these self-reactive T cells. [14][15][16][17][18][19] Previously, we illustrated the evidence of molecular mimicry at the T-cell clonal level in PBC; one molecular mimicry peptide derived from Escherichia coli PDC-E2 activated a human PDC-E2 163-176 -reactive cloned T-cell line generated from a patient with PBC. 11 In addition, we illustrated the evidence of cross-recognition of human OGDC-E2 100-113 peptide (DEVVCEIETDKTSV), which is a distinct but related mitochondrial antigen recognized by some AMAs, by human PDC-E2 163-176 -reactive cloned T-cell lines established from PBC patients.…”

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confidence: 99%

Fine Specificity of T Cells Reactive to Human PDC-E2 163-176 Peptide, the Immunodominant Autoantigen in Primary Biliary Cirrhosis: Implications for Molecular Mimicry and Cross-Recognition Among Mitochondrial Autoantigens

Shigematsu

2000

Hepatology

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The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T-cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor ( Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterized by the presence of anti-mitochondrial antibodies (AMAs) and inflammation of interlobular bile ducts. 1 The major mitochondrial antigens recognized by AMAs have been identified as E2 components of the 2-oxo acid dehydrogenase complexes including PDC-E2, OGDC-E2 and BCOADC-E2, and E3BP, all localized to the inner membrane of mitochondria. 2-10 Previously, we showed that the human PDC-E2 163-176 peptide (GDLLAEIETDKATI) is an immunodominant T-cell epitope restricted by HLA DR53 (DRA1*0101/DRB4*0101) in patients with PBC. 11 The frequency of T cells in the peripheral blood with specificity for this epitope was significantly higher in patients with PBC as compared with healthy subjects. 12 Of particular interest, the precursor frequency of PDC-E2 163-176 -reactive T cells is 100-to 150-fold higher in the liver and regional hepatic lymph nodes as compared with peripheral blood mononuclear cells (PBMCs) in patients with PBC. 13 Furthermore, these cloned T-cell lines proliferated in response to the purified native PDC-E2 protein, indicating that PDC-E2 163-176 is not a cryptic epitope. 13 Collectively, these data provide suggestive evidence for a major role of the PDC-E2 163-176 peptide in the pathogenesis of PBC. [11][12][13] T cells specific to self-antigens are incriminated in the pathogenesis of various human autoimmune diseases. Molecular mimicry between foreign and self-antigens have been implicated as a possible mechanism for the activation of these self-reactive T cells. 14-19 Previously, we illustrated the evidence of molecular mimicry at the T-cell clonal level in PBC; one molecular mimicry peptide derived from Escherichia coli PDC-E2 activated a human PDC-E2 163-176 -reactive cloned T-cell line generated from a patient with PBC. 11 In addition, we illustrated the evidence of cross-recognition of human OGDC-E2 100-113 peptide (DEVVCEIETDKTSV), which is a distinct but related mitochondrial antigen recognized by some AMAs, by human PDC-E2 163-176 -reactive cloned T-cell lines established from PBC patients. 13 In the present study, to address questions related to molecular mimicry, sharing of recognition motifs among mitochondrial antigens, T-cell receptor (TCR) antagonism or anergy, and the role of complementarity-...

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“…The pathogenic importance of the latter recognition has led us to investigate the structural basis of this cross-reactivity. While many structural studies of multiple peptide recognition on a single self-MHC molecule exist (10,11), precedents for dual MHC recognition by one TCR involve alloreactivity (12) or xenoreactivity (13).…”

mentioning

confidence: 99%

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu

Horváth

Matsumoto

et al. 2000

The Journal of Immunology

Self Cite

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KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42–56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282–294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR’s dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor’s cross-reactivity critically depends upon a TCR contact residue completely conserved in the foreign and self peptides. Further, the altered recognition of peptide derives from discrete differences on the MHC recognition surfaces and not the disparate binding grooves. This work provides a detailed structural comparison of an autoreactive TCR’s interactions with naturally occurring peptides on distinct MHC molecules. The capacity to interact with multiple self-MHCs in this manner increases the number of potentially pathogenic self-interactions available to a T cell.

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Specific T cell recognition of minimally homologous peptides: Evidence for multiple endogenous Ligands

Cited by 198 publications

References 63 publications

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

Fine Specificity of T Cells Reactive to Human PDC-E2 163-176 Peptide, the Immunodominant Autoantigen in Primary Biliary Cirrhosis: Implications for Molecular Mimicry and Cross-Recognition Among Mitochondrial Autoantigens

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

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