T Cell Activation by Lipopeptide Antigens

Moody, D. Branch; Young, David C.; Cheng, Tan-Yun; Rosat, Jean-Pierre; Roura-Mir, Carme; O’Connor, Peter B.; Zajonc, Dirk M.; Walz, Andrew J.; Miller, Marvin J.; Levery, Steven B.; Wilson, Ian A.; Costello, Catherine E.; Brenner, Michael B.

doi:10.1126/science.1089353

Cited by 245 publications

(209 citation statements)

References 34 publications

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“…About 10 years ago, nongenomically encoded, mycobactin-related lipopeptides were identified as a novel class of CD1a-restricted Ags (33). However, the strong reactivity to CME that we previously observed in humans was MHC-II restricted (22), and the loss of reactivity after proteinase K digestion, which preferentially cleaves peptide bonds following an alanine residue (34), indicate that the epitopes recognized by CME-reactive T cells have a true peptide backbone.…”

Section: Discussionmentioning

confidence: 99%

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Kaufmann

Spohr

Battenfeld

et al. 2016

The Journal of Immunology

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A new class of highly antigenic, MHC-II–restricted mycobacterial lipopeptides that are recognized by CD4-positive T lymphocytes of Mycobacterium tuberculosis–infected humans has recently been described. To investigate the relevance of this novel class of mycobacterial Ags in the context of experimental bacille Calmette-Guérin (BCG) vaccination, Ag-specific T cell responses to mycobacterial lipid and lipopeptide-enriched Ag preparations were analyzed in immunized guinea pigs. Lipid and lipopeptide preparations as well as complex Ag mixtures, such as tuberculin, mycobacterial lysates, and culture supernatants, all induced a similar level of T cell proliferation. The hypothesis that lipopeptide-specific T cells dominate the early BCG-induced T cell response was corroborated in restimulation assays by the observation that Ag-expanded T cells specifically responded to the lipopeptide preparation. A comparative analysis of the responses to Ag preparations from different mycobacterial species revealed that the antigenic lipopeptides are specific for strains of the M. tuberculosis complex. Their intriguing conservation in pathogenic tuberculous bacteria and the fact that these highly immunogenic Ags seem to be actively released during in vitro culture and intracellular infection prompt the urgent question about their role in the fine-tuned interplay between the pathogen and its mammalian host, in particular with regard to BCG vaccination strategies.

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Section: Discussionmentioning

confidence: 99%

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Kaufmann

Spohr

Battenfeld

et al. 2016

The Journal of Immunology

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“…It was possible to distinguish between these potential mechanisms by using T cells, which specifically recognize lipid Ags that are made by M. tuberculosis in vivo, but are not produced at detectable levels under the nonpermissive conditions of in vitro growth used to prepare these M. tuberculosis lipid extracts. These Ags were C 80 GMM, a CD1b-presented Ag that is processed in late endosomal compartments (23), and DDM, a CD1a-presented Ag that requires internalization into early endosomal compartments before being recognized (5,25). Monocytes that were pretreated with M. tuberculosis lipid for 3 days and then pulsed with GMM or DDM Ags were found to activate Ag-specific T cells, but untreated monocytes pulsed with Ag did not (Fig.…”

Section: Tuberculosis Lipid Stimulates Lipid Ag Uptake and Processingmentioning

confidence: 99%

“…We initially focused on M. tuberculosis because this prevalent and deadly pathogen produces many types of lipid Ags that are presented by the CD1 system, including mycolic acids, GMM, LAM, mannosyl phosphomycoketides, acylated sulfotrehaloses, and DDM lipopeptides (3,4,(5)(6)(7)(8)(9)29). Furthermore, prior studies had shown that human myeloid cells that migrate to the sites of cutaneous infection by Mycobacterium leprae or pulmonary infection by M. tuberculosis infection express CD1a, CD1b, or CD1c (30 -32).…”

mentioning

confidence: 99%

“…CD1 proteins present a variety of pathogen-derived lipids to T cells in vitro (1)(2)(3)(4)(5)(6), and T cells reactive to mycobacterial lipid Ags have been isolated from the bloodstream of tuberculosis patients, providing evidence that CD1 and lipid-reactive T cells normally function in the host response during infections with Mycobacterium tuberculosis (7)(8)(9). However, CD1-mediated T cell responses are not limited only to foreign pathogens, as endogenous mammalian phosphatidylinositols normally bind to cellular CD1 proteins as they traverse the secretory pathway (10,11), and self gangliosides, phosphatidylinositols, sulfatides, and isoglobosides activate CD1-restricted T cells (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

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Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

Roura-Mir

Wang

Cheng

et al. 2005

The Journal of Immunology

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113

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Mycobacterium tuberculosis remains a major pathogen of worldwide importance, which releases lipid Ags that are presented to human T cells during the course of tuberculosis infections. Here we report that cellular infection with live M. tuberculosis or exposure to mycobacterial cell wall products converted CD1− myeloid precursors into competent APCs that expressed group 1 CD1 proteins (CD1a, CD1b, and CD1c). The appearance of group 1 CD1 proteins at the surface of infected or activated cells occurred via transcriptional regulation, and new CD1 protein synthesis and was accompanied by down-regulation of CD1d transcripts and protein. Isolation of CD1-inducing factors from M. tuberculosis using normal phase chromatography, as well as the use of purified natural and synthetic compounds, showed that this process involved polar lipids that signaled through TLR-2, and we found that TLR-2 was necessary for the up-regulation of CD1 protein expression. Thus, mycobacterial cell wall lipids provide two distinct signals for the activation of lipid-reactive T cells: lipid Ags that activate T cell receptors and lipid adjuvants that activate APCs through TLR-2. These dual activation signals may represent a system for selectively promoting the presentation of exogenous foreign lipids by those myeloid APCs, which come into direct contact with pathogens.

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“…2). Didehydroxymycobactins are lipopeptides presented by CD1a, and are composed of a complex peptidic head group linked to a single alkyl chain of approximately 20 carbons [2].…”

Section: Structure Of Exogenous and Self-lipid Antigensmentioning

confidence: 99%

The cellular and biochemical rules of lipid antigen presentation

2009

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The recognition of both protein and lipid antigens follows similar strategies that rely on different molecular mechanisms. APC present lipid antigens exploiting the same mechanisms implicated in lipid translocation, lipoprotein assembly and lipid degradation. An important issue is how the lipid structure contributes to antigenicity. Lipid hydrophobicity influences the modes of internalization by APC, the trafficking through different membrane compartments, the binding to CD1 molecules and the stability of antigenic complexes. Some glycolipids with large hydrophilic parts require processing of the sugar moieties exerted by lysosomal hydrolases. Finally, extraction of lipids from membranes, their solubilization and loading on CD1 molecules are facilitated by the same lysosomal lipid-binding proteins that are also instrumental in lipid catabolism. More recent investigations reveal how lipid-specific immunity is regulated during infections. In this review we describe the main cellular and biochemical rules of lipid antigen presentation and discuss their implications in anti-microbial and autoimmune responses.Key words: Antigen recognition . CD1 . Lipid antigens . TCR IntroductionMembers of the MHC or CD1 families present protein and lipid antigens to T cells, respectively. CD1 molecules are differentially expressed by a variety of cell types including DC, B cells, monocytes, Langerhans cells, stellate hepatic cells, epithelial cells, microglial cells and keratinocytes. In humans, five genes (CD1A, B, C, D and E) encode CD1 proteins. CD1a, CD1b, CD1c and CD1d molecules reach the plasma membrane and are involved in lipid presentation to T cells, whereas CD1e remains intracellular and is involved in lipid processing. Lipid-specific T cells express a variety of TCR heterodimers, with the exception of invariant NKT (iNKT) cells, a CD1d-restricted population that uses a semi-invariant TCR (invariant Va24-Ja18 and variable Vb11 chains in humans, invariant Va14-Ja18 and variable Vb8.2, Vb7 or Vb2 chains in mice).Proteins become antigenic after a series of events starting with partial degradation by the cellular machinery represented by the proteasome or by proteases located in lysosomes (Ly) and endoplasmic reticulum (ER). This immunological function, commonly known as antigen processing, leads to the generation of peptide fragments that are carried to the proximity of MHC molecules with which they form antigenic complexes. A similar scheme applies to the presentation of lipid antigens. Lipids derived from extracellular routes are internalized or alternatively, self-lipid antigens are synthesized within the APC. These lipids are then transported into the cellular compartments where CD1 molecules traffic and after loading onto CD1, form antigenic complexes.The physicochemical properties of lipids and peptides impose the utilization of different strategies by the APC to digest, transport and load each of these classes of molecules. Antigenicity of lipids is achieved with the participation of extracellular and intracellular li...

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T Cell Activation by Lipopeptide Antigens

Cited by 245 publications

References 34 publications

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

The cellular and biochemical rules of lipid antigen presentation

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