Rational design of a hydrolysis-resistant mycobacterial phosphoglycolipid antigen presented by CD1c to T cells
| Autor: | Gijsbert A. van der Marel, Dennis Dam, Laura Marino, Jamie Rossjohn, D. Branch Moody, Jeroen D. C. Codée, Tan-Yun Cheng, Ildiko Van Rhijn, Thinh-Phat Cao, Josephine F. Reijneveld, Martin D. Witte, Dmitri V. Filippov, Adriaan J. Minnaard, Adam Shahine, Sara Suliman |
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| Přispěvatelé: | Immunologie, dI&I RA-I&I I&I, Chemical Biology 2 |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Antigenicity
protein crystallization T-Lymphocytes Antigen presentation CD1 Major histocompatibility complex Crystallography X-Ray CD1c Biochemistry Epitope PM phosphomycoketide Antigens CD1 Pks12 polyketide synthase 12 Antigen T‐cell receptor (TCR) Humans MHC major histocompatibility complex lipid synthesis Antigen-presenting cell Molecular Biology Phospholipids Cell Line Transformed Glycoproteins Antigens Bacterial biology Antigen processing Chemistry TCR T cell receptor MPM mannosyl-β1-phosphomycoketide T-cell receptor (TCR) Mycobacterium tuberculosis Cell Biology GMM glucose monomycolate antigen presentation biology.protein Glycolipids glycolipid HD healthy donor MDDC monocyte-derived dendritic cell Research Article |
| Zdroj: | Journal of Biological Chemistry, 297(4) Journal of Biological Chemistry, 297(4), 1. American Society for Biochemistry and Molecular Biology Inc. The Journal of Biological Chemistry Journal of Biological Chemistry, 297(4):101197. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| ISSN: | 0021-9258 |
| Popis: | Whereas proteolytic cleavage is crucial for peptide presentation by classical major histocompatibility complex (MHC) proteins to T cells, glycolipids presented by CD1 molecules are typically presented in an unmodified form. However, the mycobacterial lipid antigen mannosyl-β1-phosphomycoketide (MPM) may be processed through hydrolysis in antigen presenting cells, forming mannose and phosphomycoketide (PM). To further test the hypothesis that some lipid antigens are processed, and to generate antigens that lead to defined epitopes for future tuberculosis vaccines or diagnostic tests, we aimed to create hydrolysis-resistant MPM variants that retain their antigenicity. Here, we designed and tested three different, versatile synthetic strategies to chemically stabilize MPM analogs. Crystallographic studies of CD1c complexes with these three new MPM analogs showed anchoring of the lipid tail and phosphate group that is highly comparable to nature-identical MPM, with considerable conformational flexibility for the mannose head group. MPM-3, a difluoromethylene-modified version of MPM that is resistant to hydrolysis showed altered recognition by cells, but not by CD1c proteins, supporting the cellular antigen processing hypothesis. Furthermore, the synthetic analogs elicited T cell responses that were cross-reactive with nature-identical MPM, fulfilling important requirements for future clinical use. |
| Databáze: | OpenAIRE |
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