Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes

Paepe, Diane Cala‐De; Layre, Emilie; Giacometti, Gaëlle; Garcia-Alles, Luis F.; Mori, Lucia; Hanau, Daniel; Libero, Gennaro De; Salle, Henri; Puzo, Germain; Gilleron, Martine

doi:10.1074/jbc.m112.386300

Cited by 28 publications

(20 citation statements)

References 30 publications

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“…Cell-mediated immune responses to lipid antigens are more commonly assessed by enzyme-linked immunosorbent spot (ELISpot) assay, with incubation times of at least 48 h required before measurable responses become apparent (24,28). Further, the requirement for antigen processing and presentation of specific PIMs has been demonstrated previously (20); perhaps the most likely explanation for the discrepancy between whole-blood and PBMC IFN-␥ responses is that the frequencies of lipid-responsive cells are low and that an extended incubation allows for expansion of these cells. This is supported by our demonstration of strong proliferative responses induced after stimulation of PBMC with PIMs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

Pirson¹,

Engel²,

Gj³

et al. 2014

Clin. Vaccine Immunol.

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M embers of the mycobacterial genus are renowned for their waxy, lipid-rich outer envelope. Under physiological conditions, this outer layer is likely to be the first point of contact between the bacterial cell and the host's immune system, and the outcome of this interaction is pivotal in the establishment of infection. One of the most important groups of membrane bound lipids consists of the phosphatidylinositol mannosides (PIMs). Interest in PIMs was stimulated since it was shown that phosphatidylinositol dimannoside (PIM 2 ) forms the phosphoglycolipid anchor which tethers a large array of glycolipids and lipoglycans, including lipomannan (LM) and lipoarabinomannan (LAM), to the cellular membrane (1). PIMs have been shown to interact with a variety of immune components and mediate significant effects on the host. Ever since the realization that NKT cells could respond to lipid antigens (2-4) and the subsequent discovery of the CD1d-restricted lipid antigen ␣-galactosylceramide (␣-GalCer) (5, 6), much research effort has been concentrated on understanding lipid antigens. Although work was initially focused on invariant NKT cells, it has since been shown that great diversity exists in the lipid-responsive T cell receptor (TCR) repertoire (7-9) and that these diverse NKT cells contribute to the Th1/Th2 balance (7, 10). It has been shown that CD1d-restricted NKT cells are capable of recognizing a variety of lipid antigens, including phospholipids (11). More recently, a CD1b-restricted subset of T cells has been found (12). Similarly to CD1d-restricted invariant NKT (iNKT) cells, the CD1b-restricted variant cells require CD1B for their development and produce proinflammatory cytokines in response to CD1b-expressing dendritic cells (DCs) (12). It is clear that NKT-like cells have a significant role to play in lipid-mediated responses, and the hunt for their antigens has continued (13-15).Given the ability of lipid molecules to generate responses in peripheral blood mononuclear cells (PBMC), we decided to assess the ability of individual, highly purified natural PIMs to activate bovine lymphocytes. In this study, we developed a novel extraction method which allowed us to extract and highly purify a variety of PIM molecules from virulent Mycobacterium tuberculosis H37Rv. The ability of these molecules to induce lymphocyte responses in Mycobacterium bovis-infected cattle was investigated by measuring lymphocyte proliferation and gamma interferon (IFN-␥) production. Furthermore, flow cytometry techniques were utilized to characterize responding cell populations. MATERIALS AND METHODS Extraction of PIMs.Using the novel methodology outlined below, highly pure phosphatidylinositol dimannoside (PIM 2 ), acylphosphatidylinositol dimannoside (AcPIM 2 ), diacyl-phosphatidylinositol dimannoside (Ac 2 PIM 2 ), acylphosphatidylinositol hexamannoside (AcPIM 6 ), and diacylphosphatidylinositol hexamannoside (Ac 2 PIM 6 ) were successfully isolated. Individual PIM molecules were analyzed by electrospray ionization mass spectrometr...

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Section: Discussionmentioning

confidence: 99%

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

Pirson¹,

Engel²,

Gj³

et al. 2014

Clin. Vaccine Immunol.

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“…In the ER, the microsomal triglyceride transfer protein performs these functions [83], while in the endocytic pathway saposins are active [84–86]. The lysosomal lipid transfer molecule CD1e has been demonstrated to be required for the presentation of phosphatidylinositol mannoside as well as its chemical modification [79,87]. …”

Section: Recognition Of Lipid-based Ags By Group 1 Cd1-restricted T-cmentioning

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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“…Finally, in addition to their involvement in innate immune mechanisms, PIMs, LM and ManLAM are also recognized as antigens by the adaptative immune system upon presentation to T-lymphocytes by MHC-I-like molecules of the CD1 family. Biochemical and structural studies have begun to elucidate the molecular basis of their processing and presentation (Porcelli and Modlin, 1999; Fischer et al ., 2004; de la Salle et al ., 2005; Torrelles et al ., 2004; Torrelles et al ., 2011; Garcia-Alles et al ., 2011; Torrelles et al ., 2012; Cala-De Paepe et al ., 2012). …”

Section: The Major Cell Envelope Glycoconjugates Of Mtbmentioning

confidence: 99%

The cell envelope glycoconjugates ofMycobacterium tuberculosis

Angala

Belardinelli

Huc-Claustre

et al. 2014

Critical Reviews in Biochemistry and Molecular Biology

122

191

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Tuberculosis (TB) remains the second most common cause of death due to a single infectious agent. The cell envelope of Mycobacterium tuberculosis (Mtb), the causative agent of the disease in humans, is a source of unique glycoconjugates and the most distinctive feature of the biology of this organism. It is the basis of much of Mtb pathogenesis and one of the major causes of its intrinsic resistance to chemotherapeutic agents. At the same time, the unique structures of Mtb cell envelope glycoconjugates, their antigenicity and essentiality for mycobacterial growth provide opportunities for drug, vaccine, diagnostic and biomarker development, as clearly illustrated by recent advances in all of these translational aspects. This review focuses on our current understanding of the structure and biogenesis of Mtb glycoconjugates with particular emphasis on one of most intriguing and least understood aspect of the physiology of mycobacteria: the translocation of these complex macromolecules across the different layers of the cell envelope. It further reviews the rather impressive progress made in the last ten years in the discovery and development of novel inhibitors targeting their biogenesis.

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Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes

Cited by 28 publications

References 30 publications

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

Molecular recognition of microbial lipid-based antigens by T cells

The cell envelope glycoconjugates ofMycobacterium tuberculosis

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