Dynamic properties of MHC class II allotypes
Final Report Abstract
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/).
Publications
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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 M, Morrison E, Abualrous ET, Kuropka B, Freund C
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(2020). CD4+ Th immunogenicity of the Ascaris spp. secreted products. npj Vaccines 5, 25
Ebner F, Morrison E, Bertazzon M, Midha A, Hartmann S, Freund C, Álvaro-Benito M
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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 M, Morrison E, Ebner F, Abualrous ET, Urbicht M, Wieczorek M, Freund C
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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 AM, Virdis F, Morrison E, Álvaro-Benito M, Khan AA, Freund C, Golovkina TV, Denzin LK
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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 H, Abualrous ET, Sticht J, Fernandez LMA, Werk T, Weise C, Ballaschk M, Schmieder P, Loll B, Freund C
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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 E, Lupoli G, Füchsl F, Abualrous ET, de Andrade Krätzig N, Gosmann D, Wietbrock L, Lange S, Engleitner T, Lan H, Audehm S, Effenberger M, Boxberg M, Steiger K, Chang Y, Yu K, Atay C, Bassermann F, Weichert W, Busch DH, Rad R, Freund C, Antes I, Krackhardt AM
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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 ET, Sticht J, Freund C
