Structural bases for MHC class I peptide selection and neoepitope formation
Author: Hafstrand, Ida
Date: 2018-05-04
Location: Fire lecture hall, Science for Life Laboratory, Tomtebodavägen 23, Stockholm
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (2.069Mb)
Abstract
One task of the immune system is to distinguish between healthy cells and altered cells due to
viruses or cancers. To achieve this CD8+ T-cells are constantly monitoring the Major
histocompatibility class I (MHC-I) complexes expressed on all nucleated cells in the body.
The MHC-I is basically a scaffold to hold and display a short (usually 8-10 amino acids)
peptide. These peptides are selected by a complicated machinery from the total peptidome as
formed by the proteolytic activity in the cells. The peptides derive from the proteome within
the cells, which is degraded by the proteasome to peptides of various lengths. These are
transported into the endoplasmic reticulum (ER) by the transporters associated with antigen
processing (TAP). Inside the ER, the peptides can be further processed by the ER
aminopeptidases (ERAP1 and ERAP 2) before being loaded into the MHC-I by the peptide
loading complex (PLC). The peptide loading complex consists of tapasin, ERp57 and
calreticulin. The peptide MHC-I complex (pMHC-I) is then transported to the cell surface
where they can be presented to the T-Cells of the immune system. The T-cells express the
highly variable T-cell Receptor (TCR) which are formed from recombining the V(D)J
segment in the TCR gene. The T-cells are selected in the Thymus, where self-responding Tcells are killed and the remaining, with low affinity to self, continue into circulation. This
ensures protection against autoimmunity, T-cell responses against healthy cells. Cancer-cell
survival and proliferation require immune system escape and consequently many cancer cells
have deficiencies in the processing system.
In this thesis four studies are presented. The first concerns the mechanism of tapasin influence on the peptide selection and loading into the peptide binding cleft of the MHC-I. In this study, a leucine on a loop of tapasin is shown to be able to bind into the F-pocket of the peptide binding cleft, and influence the peptide loading of the MHC-I.
The second study is about a neoepitope that is presented on TAP-deficient cancer cells. This peptide, Trh4, was the first identified TEIPP (T-cell epitopes associated with impaired peptide processing). As a murine H-2Db restricted peptide is has an unusual sequence, containing four sulphur containing residues of the total nine. Here, we show the formation and importance of sulphur-π interaction for complex stability and the unconventional methionine at peptide position 5 for the formation of TCR interaction.
The third study is a follow-up on the second study, but here the immunogenicity of the peptide is in focus. While the wild-type Trh4 peptide displays low immunogenicity, the mutation of peptide position 3 to a proline significantly increase the immunogenicity of this epitope. However, the increased immunogenicity is surprisingly not related to increased stability of the pMHC-I complex.
In the final paper, two virus-associated epitopes are studied due to their differences in immunogenicity and binding to MHC-I. Both peptides carry a glycosylation motif and are glycosylated in the source protein. Here we show the structural basis for the discrepancy between the peptides. The glycosylated residue in one peptide (GP92) is protruding from the peptide binding cleft free for interaction with a TCR, while for the other peptide (GP392), a glycosylation would hinder the utilisation of a dominant anchor residue of the peptide for peptide binding to the MHC-I.
In this thesis four studies are presented. The first concerns the mechanism of tapasin influence on the peptide selection and loading into the peptide binding cleft of the MHC-I. In this study, a leucine on a loop of tapasin is shown to be able to bind into the F-pocket of the peptide binding cleft, and influence the peptide loading of the MHC-I.
The second study is about a neoepitope that is presented on TAP-deficient cancer cells. This peptide, Trh4, was the first identified TEIPP (T-cell epitopes associated with impaired peptide processing). As a murine H-2Db restricted peptide is has an unusual sequence, containing four sulphur containing residues of the total nine. Here, we show the formation and importance of sulphur-π interaction for complex stability and the unconventional methionine at peptide position 5 for the formation of TCR interaction.
The third study is a follow-up on the second study, but here the immunogenicity of the peptide is in focus. While the wild-type Trh4 peptide displays low immunogenicity, the mutation of peptide position 3 to a proline significantly increase the immunogenicity of this epitope. However, the increased immunogenicity is surprisingly not related to increased stability of the pMHC-I complex.
In the final paper, two virus-associated epitopes are studied due to their differences in immunogenicity and binding to MHC-I. Both peptides carry a glycosylation motif and are glycosylated in the source protein. Here we show the structural basis for the discrepancy between the peptides. The glycosylated residue in one peptide (GP92) is protruding from the peptide binding cleft free for interaction with a TCR, while for the other peptide (GP392), a glycosylation would hinder the utilisation of a dominant anchor residue of the peptide for peptide binding to the MHC-I.
List of papers:
I. Successive crystal structure snapshots reveal the bases for MHC class I peptide binding and editing. Hafstrand I, Apavaloaei A, Sayitoglu EC, Buratto J, Pellegrino S, Han X, Sun R, Nilvebrant J, Nygren P-Å, Sandalova T, Springer S, Duru AD and Achour A. [Manuscript]
II. The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer. Hafstrand I, Doorduijn EM, Duru AD, Buratto J, Oliveira CC, Sandalova T, van Hall T, Achour A. Journal of Immunology, 2016 Mar 1;196(5):2327-34.
Fulltext (DOI)
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III. The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability. Hafstrand I, Doorduijn EM, Sun R, Talyzina A, Sluijter M, Pellegrino S, Sandalova T, Duru AD, van Hall T, Achour A. Journal of Immunology, 2018 Mar 5.
Fulltext (DOI)
Pubmed
IV. Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity. Hafstrand I, Badia-Martinez D, Josey BJ, Norstrom M, Buratto J, Pellegrino S, Duru AD, Sandalova T, Achour A. PLoS One, 2017 Dec 18;12(12):e018958.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Successive crystal structure snapshots reveal the bases for MHC class I peptide binding and editing. Hafstrand I, Apavaloaei A, Sayitoglu EC, Buratto J, Pellegrino S, Han X, Sun R, Nilvebrant J, Nygren P-Å, Sandalova T, Springer S, Duru AD and Achour A. [Manuscript]
II. The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer. Hafstrand I, Doorduijn EM, Duru AD, Buratto J, Oliveira CC, Sandalova T, van Hall T, Achour A. Journal of Immunology, 2016 Mar 1;196(5):2327-34.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability. Hafstrand I, Doorduijn EM, Sun R, Talyzina A, Sluijter M, Pellegrino S, Sandalova T, Duru AD, van Hall T, Achour A. Journal of Immunology, 2018 Mar 5.
Fulltext (DOI)
Pubmed
IV. Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity. Hafstrand I, Badia-Martinez D, Josey BJ, Norstrom M, Buratto J, Pellegrino S, Duru AD, Sandalova T, Achour A. PLoS One, 2017 Dec 18;12(12):e018958.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Achour, Adnane
Co-supervisor: Nygren, Per-Åke; Chambers, Benedict; Duru, Adil Doganay
Issue date: 2018-04-13
Rights:
Publication year: 2018
ISBN: 978-91-7676-994-2
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