A molecular switch in mouse CD1d modulates natural killer T cell activation by α-galactosylsphingamides

A Humanized Mouse Model Coupled with Computational Analysis Identifies Potent Glycolipid Agonist of Invariant NKT Cells

“…The structure of the CD1d-TCR complex consists of four protein chains: CD1d, β-2-microglobulin (β 2 m), αTCR (V α , C α ), and βTCR (V β , C β ) (Figure ). Consistent with previous publications, ,,, our analysis of the most frequent interactions shows that only two of those chains are involved in direct contacts with the glycolipids: CD1d and the invariant α-chain of the TCR (Vα14-Jα18 in wild type mice and Vα24-Jα18 in humans or VαKI mice). , To evaluate the role of each of these chains in the differential affinities among ligands in both ternary complexes (human and mouse), the average total interactions (including hydrophobic contacts, hydrogen bonds, water bridges, π–π, and π-cation) were counted and divided into two groups depending on whether they involved CD1d or TCRα (Figure C,D). Interestingly, the trends observed for binding energies were reflected by the interactions with the TCRα chain in both complexes, pointing to a key role of this part of the complex in determining the binding strength and, consequently, biological activity.…”

“…The three principal structural elements determining the recognition of glycolipids by iNKT cells are the CD1d antigen-presenting protein, the glycolipid antigen, and the iNKT cell TCR (Figure B). Crystallographic structures of mouse and human ternary complexes have been published, contributing greatly to the understanding of structural features of glycolipid antigen recognition. ,− However, a critical limitation has been the inability to develop computational strategies using biological outcomes that are relevant in a human context since most immune response stimulation assays and cancer models have been carried out in mice. It also is unclear whether ligand binding strength correlates with immune response and anticancer effects.…”

Rationally Designed Highly Potent NKT Cell Agonists with Different Cytokine Selectivity through Hydrogen-Bond Interaction

“…Nonetheless, an intensified interaction between glycolipids and CD1d has been reported to promote Th1-skewed polarization. 24,25 In line with this premise, several representative Th1-biasing ligands have been designed regarding the structure−activity relationship (SAR) of glycolipid binding to CD1d, such as αGalCer analogues with aromatic groups introduced in the fatty acyl chain, 25−29 sphingosine chain, 26,30 or hydroxyl groups on the pyranose ring. 31−33 In addition, altering the stability of the CD1d/glycolipid binary or the association between the binary and T cell receptor (TCR) was also reported to favor the production of IFN-γ.…”

“…As the prototype NKT cell-activating ligand, α-galactosylceramide (αGalCer) has been extensively studied for applications in immunotherapy , and vaccine as adjuvant, − among which conjugating αGalCer to antigens has shown effective enhancement in vaccine efficacy as other conjugate vaccines. − On the other hand, scientists are still making efforts to pursue new αGalCer analogues, as structural alterations to αGalCer have been found to profoundly shape the balance between Th1 and Th2 responses. , However, the fundamental principles governing the preferential generation of either Th1 or Th2 cytokines still remain uncovered. Nonetheless, an intensified interaction between glycolipids and CD1d has been reported to promote Th1-skewed polarization. , In line with this premise, several representative Th1-biasing ligands have been designed regarding the structure–activity relationship (SAR) of glycolipid binding to CD1d, such as αGalCer analogues with aromatic groups introduced in the fatty acyl chain, − sphingosine chain, , or hydroxyl groups on the pyranose ring. − In addition, altering the stability of the CD1d/glycolipid binary or the association between the binary and T cell receptor (TCR) was also reported to favor the production of IFN-γ. − A collection of representative αGalCer analogues with Th1-biased modifications is shown in Table S1, most of which are designed to regulate the interaction between ligands and CD1d.…”