Structures and Functions of Microbial Lipid Antigens Presented by CD1

Willcox, Benjamin E.; Willcox, Carrie R.; Dover, Lynn G.; Besra, Gurdyal S.

doi:10.1007/978-3-540-69511-0_4

Cited by 14 publications

(12 citation statements)

References 93 publications

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“…Most mycobacterial antigens that are known to be presented by CD1 are presented by group 1 CD1 (CD1a, CD1b, and CD1c), which are absent in mice. The known CD1-presented mycobacterial antigens are diverse and include mycobacterial mycolates, diacylglycerols (LAM and PIM), polyisoprenoid lipids, sulfotrehalose-containing lipids and lipopeptides [34]. Cattle express CD1a and three CD1b isoforms, but lacks CD1c [35].…”

Section: Immune Responses To Mycobacteria In Different Speciesmentioning

confidence: 99%

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

Rhijn

Godfroid

Michel

et al. 2008

Microbes and Infection

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Section: Immune Responses To Mycobacteria In Different Speciesmentioning

confidence: 99%

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

Rhijn

Godfroid

Michel

et al. 2008

Microbes and Infection

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“…The CD1-restricted T cells have been implicated in a diverse array of immune functions including host defense against pathogens, immune regulation, and autoimmunity (9,10). In addition, foreign lipids derived from bacteria, as well as self-lipid antigens, have been described for CD1 (11)(12)(13)(14)(15)(16). Although the CD1 lipid antigens are chemically diverse, the general motif for these antigens corresponds to 2 hydrophobic acyl chains that are connected to a polar head group, which usually is a carbohydrate moiety (17).…”

mentioning

confidence: 99%

The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

Zajonc

Striegl

Dascher

et al. 2008

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

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The molecular details of glycolipid presentation by CD1 antigenpresenting molecules are well studied in mammalian systems. However, little is known about how these non-classical MHC class I (MHCI) molecules diverged from the MHC locus to create a more complex, hydrophobic binding groove that binds lipids rather than peptides. To address this fundamental question, we have determined the crystal structure of an avian CD1 (chCD1-2) that shares common ancestry with mammalian CD1 from Ϸ310 million years ago. The chCD1-2 antigen-binding site consists of a compact, narrow, central hydrophobic groove or pore rather than the more open, 2-pocket architecture observed in mammalian CD1s. Potential antigens then would be restricted in size to single-chain lipids or glycolipids. An endogenous ligand, possibly palmitic acid, serves to illuminate the mode and mechanism of ligand interaction with chCD1-2. The palmitate alkyl chain is inserted into the relatively shallow hydrophobic pore; its carboxyl group emerges at the receptor surface and is stabilized by electrostatic and hydrogen bond interactions with an arginine residue that is conserved in all known CD1 proteins. In addition, other novel features, such as an A loop that interrupts and segments the normally long, continuous ␣1 helix, are unique to chCD1-2 and contribute to the unusually narrow binding groove, thereby limiting its size. Because birds and mammals share a common ancestor, but the rate of evolution is slower in birds than in mammals, the chCD1-2-binding groove probably represents a more primordial CD1-binding groove.evolution ͉ glycolipid

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“…These data suggest strongly that the antigen recognized by CTLs is lipid in nature. Because this antigen is a mixture of bacterial lipids and as a number of mycobacterial lipids and glycolipids have been shown to be presented via the CD1 antigen-presenting system (Bricard & Porcelli, 2007;Willcox et al, 2007), we sought to fractionate and characterize the recognized lipids further.…”

Section: Resultsmentioning

confidence: 99%

“…Genome sequencing has confirmed the phylogenetic relationship between the two pathogens and shown that, like M. tuberculosis, a significant percentage of R. equi genes are involved in lipid metabolism (Rahman et al, 2003). The characteristic cell-wall lipids of these organisms have a number of critical functions and, importantly, are the end products of complex biochemical pathways (Brennan & Nikaido, 1995;Willcox et al, 2007). As a result, the unique lipids that are produced by these bacteria do not lend themselves to antigen variation in the same way that surface proteins of many pathogens can (Bricard & Porcelli, 2007).…”

Section: Discussionmentioning

confidence: 99%

Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes

et al. 2010

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Immune adult horses have CD8 + cytotoxic T lymphocytes (CTLs) that recognize and lyse Rhodococcus equi-infected cells in an equine lymphocyte alloantigen (ELA)-A [classical major histocompatibility complex (MHC) class I]-unrestricted fashion. As protein antigens are MHC class I-restricted, the lack of restriction suggests that the bacterial antigens being recognized by the host are not proteins. The goals of this study were to test the hypothesis that these CTLs recognize unique R. equi cell-wall lipids related to mycobacterial lipids. Initial experiments showed that treatment of soluble R. equi antigen with broadly reactive proteases did not significantly diminish the ability of the antigen to stimulate R. equi-specific CTLs. R. equi-specific CTLs were also shown to lyse target cells (equine macrophages) pulsed with an R. equi lipid extract. Analysis of the R. equi lipid by TLC and MS (MALDI-TOF and ES) indicated that the extracted antigen consisted of three primary fractions: trehalose monomycolate (TMM), trehalose dimycolate (TDM) and cardiolipin (CL). ELA-A-mismatched cells pulsed with purified TMM and CL, but not the TDM fraction, were recognized and lysed by R. equi-specific CTLs. Because of their role in immune clearance and pathogenesis, transcription of the cytokines gamma interferon (IFN-c) and interleukin-4 (IL-4) was also measured in response to R. equi lipids by using real-time PCR; elevated IFN-c, but not IL-4, was associated with host clearance of the bacteria. The whole-cell R. equi lipid and all three R. equi lipid fractions resulted in marked increases in IFN-c transcription, but no increase in IL-4 transcription. Together, these data support the hypothesis that immune recognition of unique lipids in the bacterial cell wall is an important component of the protective immune response to R. equi. The results also identify potential lipid antigens not previously shown to be recognized by CTLs in an important, naturally occurring actinomycete bacterial pathogen.

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Structures and Functions of Microbial Lipid Antigens Presented by CD1

Cited by 14 publications

References 93 publications

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes

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