Dynamische Eigenschaften von Allotypen der MHC-Klasse II
Zusammenfassung der Projektergebnisse
Proteins of the major histocompatibility Complex (MHC) present antigenic peptides for the surveillance by T cells, and as a consequence enable the cellular arm of adaptive immunity. MHC proteins show a large degree of genetic variation across the human population and these polymorphism impact the peptide repertoire presented by individual variants, called allotypes. For the so-called MHC class II molecules, processing of exogenous antigens typically occurs in the late endosome. At the low pH of this compartment the MHCII-like molecule HLA-DM encounters the MHCII molecules pre-loaded with the placeholder peptide CLIP. HLA-DM catalyzes peptide exchange, giving rise to stable peptide-MHCII complexes that are transported to the cell surface. Mechanistically, HLA-DM exploits dynamic features of MHCII that are altered by polymorphic variation. In this project we provide a comprehensive study of HLA- DR allotypes with regard to their dynamics and HLA-DM susceptibilities. We show that replacement of the placeholder peptide CLIP varies by a factor of ten between MHCII allotypes and that the propensity to occupy a rare dynamic intermediate accounts in part for the observed differences in exchange rates. Polymorphisms along the peptide binding groove affect the occupancy of certain conformational states of MHCII-CLIP complexes as shown by MD simulations and Markov state modeling. NMR experiments confirm that HLA-DM binding coincides with conformational dynamics and double-mutant-cycle analysis reveals allosteric coupling between polymorphic sites. Thus, dynamic feature and occupancy of excited states, a requirement for HLA-DM catalysis, are maintained even in the presence of many polymorphisms and for thermodynamically stable MHCII-peptide complexes. However, the occurrence of the conformational states is influenced by polymorphisms and thereby affects HLA-DM-catalysis and thus the presented peptide repertoire. At the cellular level, we have established an efficient mass spectrometrybased algorithm to simplify and deconvolute the complex and ambiguous peptide-level dataset from cellular immunopeptidomes by grouping identified peptides into epitopes that are subsequently analyzed. This PLAtEAU software (for Peptide Landscape Antigenic Epitope Alignment Utility) is available as a Webbased tool at our university (https://plateau.bcp.fu-berlin.de/).
Projektbezogene Publikationen (Auswahl)
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(2018) Quantification of HLA-DM- Dependent Major Histocompatibility Complex of Class II Immunopeptidomes by the Peptide Landscape Antigenic Epitope Alignment Utility. Front Immunol. 9:872
Álvaro-Benito, Miguel; Morrison, Eliot; Abualrous, Esam T.; Kuropka, Benno & Freund, Christian
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(2020). Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation. Cell Mol Immunol 17(2):133-142
Álvaro-Benito, Miguel; Morrison, Eliot; Ebner, Friederike; Abualrous, Esam T.; Urbicht, Marie; Wieczorek, Marek & Freund, Christian
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(2020). CD4+ Th immunogenicity of the Ascaris spp. secreted products. npj Vaccines 5, 25
Ebner, Friederike; Morrison, Eliot; Bertazzon, Miriam; Midha, Ankur; Hartmann, Susanne; Freund, Christian & Álvaro-Benito, Miguel
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(2020). Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA that Have Altered Function. J Immunol. 205(4):923-935.
Graves, Austin M.; Virdis, Francesca; Morrison, Eliot; Álvaro-Benito, Miguel; Khan, Aly A.; Freund, Christian; Golovkina, Tatyana V. & Denzin, Lisa K.
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(2021). Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules (2021). Nature Communications 12, 4236
Lan, Huan; Abualrous, Esam T.; Sticht, Jana; Fernandez, Laura Maria Arroyo; Werk, Tamina; Weise, Christoph; Ballaschk, Martin; Schmieder, Peter; Loll, Bernhard & Freund, Christian
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(2021). Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma. J Immunother Cancer 9 e002754
Bräunlein, Eva; Lupoli, Gaia; Füchsl, Franziska; Abualrous, Esam T.; De Andrade Krätzig, Niklas; Gosmann, Dario; Wietbrock, Lukas; Lange, Sebastian; Engleitner, Thomas; Lan, Huan; Audehm, Stefan; Effenberger, Manuel; Boxberg, Melanie; Steiger, Katja; Chan
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(2021). Major histocompatibility complex (MHC) class I and class II proteins: impact of polymorphism on antigen presentation. Curr Opin Immunol. 70:95-104
Abualrous, Esam T; Sticht, Jana & Freund, Christian
