Abstract
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.
Highlights
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
The ability of T cells to respond to peptides presented by major histocompatibility complex (MHC) proteins is more widely known than their ability to respond to nonclassical MHC class I-like CD1 proteins
Several lipid antigens that are presented by CD1 and recognized by T cells are found in the cell wall of Mycobacterium tuberculosis
Summary
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. The mycobacterial lipid antigen mannosyl-β1-phosphomycoketide (MPM) may be processed through hydrolysis in antigen presenting cells, forming mannose and phosphomycoketide (PM). Bypassing the cellular component of antigen presentation, using plate-bound CD1c, it was shown that the T cell receptor (TCR) was specific for PM and not MPM [12]. These studies suggested that MPM underwent “lipid antigen processing” to form PM by the cellular CD1c antigen presentation machinery, raising the questions whether lipid antigen processing by cells occurs generally and whether lipid antigens provided in vaccines or in vitro diagnostic tests might be recognized in another form. Re-engineering of the head group might affect T cell recognition
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