Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

Abstract

Invariant natural killer T cell (NKT) cells (iNKT cells) produce both T-helper 1 (Th1) and T-helper 2 cytokines in response to α-Galactosylceramide (α-GalCer) stimulation and are thought to be the important effectors in the regulation of both innate and adaptive immunity involved in autoimmune disorders, microbial infections, and cancers. However, the anticancer effects of α-GalCer were limited in early clinical trial. In this study, several analogs of α-GalCer, containing phenyl groups in the lipid tails were found to stimulate murine and human iNKT cells to secrete Th1-skewed cytokines and exhibit greater anticancer efficacy in mice than α-GalCer. We explored the possibility of different Vβ usages of murine Vα14 iNKT or human Vα24 iNKT cells, accounting for differential cytokine responses. However, T-cell receptor Vβ analysis revealed no significant differences in Vβ usages by α-GalCer and these phenyl glycolipid analogs. On the other hand, these phenyl glycolipids showed greater binding avidity and stability for iNKT T-cell receptor when complexed with CD1d. These findings suggest that CD1d-phenyl glycolipid complexes may interact with the same population of iNKT cells but with higher avidity and stability to drive Th1 polarization. Thus, this study provides a key to the rational design of Th1 biased CD1d reactive glycolipids in the future.immune-modulating activity | structure | interaction | cancer immunotherapy

α-Galactosylceramide but Not Phenyl-Glycolipids Induced NKT Cell Anergy and IL-33–Mediated Myeloid-Derived Suppressor Cell Accumulation via Upregulation of egr2/3

“…To our knowledge, this study provides the first evidence that weaker TCR binding glycolipids, C1 and C17, upregulated the expression of egr-2/3 in NKT cells, which induced the immunosuppressive molecule, PD1 and cbl-b, causing NKT cell anergy. These phenomena were not observed in our phenyl-glycolipids, which had been reported to have greater TCR signaling than a-GalCer because of stronger binding avidity and greater binding stability of CD1d-phenyl glycolipid complexes for iNKT TCR (8). Our findings were in line with the report that a-GalCer induced the expression of PD1 and cbl-b, which might contribute to NKT cell anergy (9,12).…”

“…2B). This pattern was consistent with our previous report of TCR V-b-chain usage by C1 and C34 (8). Thus, the lack of NKT anergy induction by phenyl-glycolipids could not be attributed to the activation of different subsets of NKT cells.…”

“…1B, we observed that at 2 h after stimulation, a-GalCer induced less IFN-g, IL-4, and IL-2 production than phenyl-glycolipipds (except for IL-2 induction by C11). This was in line with our previous report that phenyl-glycolipids displayed greater binding avidity and stability than C1 for iNKT TCRs when complexed with CD1d, driving higher TCR signaling, Th1 polarization at 2 h and greater anticancer potency than C1 (7,8).To further support the notion that weaker binding affinity of glycolipids to TCR contributed to NKT anergy, we determined the cytokine responses in mice were treated…”

“…We previously developed many synthetic analogs of a-GalCer and reported that those containing phenyl group(s) on the lipid tail could stimulate NKT cells toward Th1 responses and exhibited more potent anticancer activities in mice than a-GalCer (7). Recently, we demonstrated that greater binding avidity and stability of ternary complexes of CD1d-glycolipid-invariant NKT (iNKT) TCR may contribute to their Th1 polarization and greater anticancer efficacy (8). What remains unclear is whether these phenylglycolipids could induce NKT cell anergy as found for a-GalCer.…”

RM2 Antigen: Synthesis of Glycoconjugates

“…Recently, Wong and co-workers evaluated the cytokine secretion profiles of 22 α-GalCer analogs, the same glycan head as α-GalCer but presence of double bond on either of the two lipids or with different chain length, and summarized in (Fig. 3.4) [40] that acyl modifications on the phenyl ring could promote Th1-biased polarization. The C34, C23, and 7DW8-5 induced higher ratio of IFN-γ to IL-4 in mice and in humans, exhibiting greater anticancer effects in mice (Figs.…”