The CD1 family: serving lipid antigens to T cells since the Mesozoic era

The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p-fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity.

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“…18,19,20 This assemblage stimulates the production of cytokines. Against this backdrop, we were interested in the new C -glycosides 7 – 10 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Altiti

Zhang

et al. 2017

Carbohydrate Research

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“…Interestingly, the bovine CD1d gene (26) and the primordial CD1-encoding gene found in chickens (27) also contain an amino acid change at position 168. This change was previously shown to affect the nature of the antigens presented by these molecules (2). Intriguingly, rats possess only one CD1D gene, which, based on sequence homology, more resemble mouse CD1D1 than CD1D2, with a cysteine at position 168 (28).…”

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confidence: 99%

“…CD1 | MHC | NKT C D1 molecules are glycoproteins that adopt an MHC class I-like structure (1). In contrast to the polymorphic MHC molecules that present peptides, CD1 molecules exhibit limited polymorphism and are ideally suited to present lipid-based antigens (2). Based on sequence homology, function, and tissue distribution, the CD1 family has been classified into three distinct groups: group I, includes CD1a, -b, and -c; group II consists of CD1d, and group III is composed of CD1e (3).…”

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confidence: 99%

“…These two genes are located on chromosome 3 and are approximately 9 kb apart, arranged in opposite transcriptional orientation (19). The two genes share 95% sequence homology with each other, and are likely the product of gene duplication (2,20). Mouse CD1d molecules are expressed primarily by cells of the hematopoietic lineage, including B and T cells, macrophages, and dendritic cells (21,22).…”

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confidence: 99%

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Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function

Sundararaj

Zhang

Krovi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A'-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.

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“…CD1e forms a third group and its function is still unclear but is believed to be involved in lipids transfer [10]. All CD1 molecules share structural similarities with the classical MHC-I molecules, but they have evolved to accommodate a chemically distinct class of Ags, namely, lipid-based Ags [11,12]. Typically, lipid-based Ags are amphipathic molecules with polar headgroups (e.g.…”

Section: Introductionmentioning

confidence: 99%

Molecular recognition of microbial lipid-based antigens by T cells

Gras

Rhijn

Shahine

et al. 2018

Cell. Mol. Life Sci.

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The immune system has evolved to protect hosts from pathogens. T cells represent a critical component of the immune system by their engagement in host defence mechanisms against microbial infections. Our knowledge of the molecular recognition by T cells of pathogen-derived peptidic antigens that are presented by the major histocompatibility complex glycoproteins is now well established. However, lipids represent an additional, distinct chemical class of molecules that when presented by the family of CD1 antigen-presenting molecules can serve as antigens, and be recognized by specialized subsets of T cells leading to antigen-specific activation. Over the past decades, numerous CD1-presented self- and bacterial lipid-based antigens have been isolated and characterized. However, our understanding at the molecular level of T cell immunity to CD1 molecules presenting microbial lipid-based antigens is still largely unexplored. Here, we review the insights and the molecular basis underpinning the recognition of microbial lipid-based antigens by T cells.

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The CD1 family: serving lipid antigens to T cells since the Mesozoic era

Cited by 24 publications

References 142 publications

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function

Molecular recognition of microbial lipid-based antigens by T cells

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