Home About us Contact
|
Home About us Contact | ||
|
|
||
Lipid Antigens (lipid + antigen)
Selected AbstractsMicrosomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group,1 CD1 moleculesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Arthur Kaser Abstract Lipid antigens are presented to T cells by the non-polymorphic MHC class,I-related CD1 molecules. Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident chaperone that has been shown to lipidate the group,2 CD1 molecule CD1d and thus to regulate its function. We now report that MTP also regulates the function of group,1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in monocyte-derived dendritic cells and lymphoblastoid B cell lines transfected with group,1 CD1 resulted in a substantial decrease in endogenous self lipid antigen presentation to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected HeLa cells similarly resulted in decreased self reactivity. Unexpectedly, inhibition of ER-resident MTP, which was confirmed by confocal microscopy, also markedly decreased presentation of exogenous, endosomally loaded, mycobacterial lipid antigens by CD1a and CD1c to T cells. Thus, these studies indicate that MTP, despite its ER localization, regulates endogenous as well as exogenous lipid antigen presentation, and suggest a broad role for MTP in the regulation of CD1 antigen presentation. [source] Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Markus Moll Abstract Invariant CD1d-restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV-1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV-1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN-, in response to CD1d-restricted lipid antigen as compared with cells from uninfected control subjects. HIV-1 infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor (CD279) on the CD4, subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD-1-independent. Furthermore, the elevated PD-1 expression and the functional defects were not restored by anti-retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT-cell compartment in HIV-1-infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients. [source] Low cross-reactivity of T-cell responses against lipids from Mycobacterium bovis and M. avium paratuberculosis during natural infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Ildiko Van Rhijn Abstract Although CD1 proteins are known to present mycobacterial lipid antigens to T cells, there is little understanding of the in vivo behavior of T cells restricted by CD1a, CD1b and CD1c, and the relative immunogenicity and immunodominance of individual lipids within the total array of lipids that comprise a bacterium. Because bovines express multiple CD1 proteins and are natural hosts of Mycobacterium bovis and Mycobacterium avium paratuberculosis (MAP), we used them as a new animal model of CD1 function. Here, we report the surprisingly divergent responses against lipids produced by these two pathogens during infection. Despite considerable overlap in lipid content, only three out of 69 animals cross-react with M. bovis and MAP total lipid preparations. The unidentified immunodominant compound of M. bovis is a hydrophilic compound, whereas the immunodominant lipid of MAP is presented by CD1b and was identified as glucose monomycolate (GMM). The preferential recognition of GMM antigen by MAP-infected cattle may be explained by the higher expression of GMM by MAP than by M. bovis. The bacterial species-specific nature of the CD1-restricted, adaptive T-cell response affects the approach to development of lipid based immunodiagnostic tests. [source] Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group,1 CD1 moleculesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Arthur Kaser Abstract Lipid antigens are presented to T cells by the non-polymorphic MHC class,I-related CD1 molecules. Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident chaperone that has been shown to lipidate the group,2 CD1 molecule CD1d and thus to regulate its function. We now report that MTP also regulates the function of group,1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in monocyte-derived dendritic cells and lymphoblastoid B cell lines transfected with group,1 CD1 resulted in a substantial decrease in endogenous self lipid antigen presentation to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected HeLa cells similarly resulted in decreased self reactivity. Unexpectedly, inhibition of ER-resident MTP, which was confirmed by confocal microscopy, also markedly decreased presentation of exogenous, endosomally loaded, mycobacterial lipid antigens by CD1a and CD1c to T cells. Thus, these studies indicate that MTP, despite its ER localization, regulates endogenous as well as exogenous lipid antigen presentation, and suggest a broad role for MTP in the regulation of CD1 antigen presentation. [source] MR1-restricted V,19i T cells , a second population recognizing lipid antigens?EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Jens Schümann Abstract There is increasing evidence that T cells recognizing lipid antigens contribute to the immunological regulation of different disease conditions including autoimmunity. The best-known subset is CD1d-restricted lipid-reactive T cells characterized by the expression of an invariant TCR, chain. Much less is known about the biology of another invariant T cell subset, which is restricted to the MHC class I-like molecule MR1. A beneficial role of MR1-restricted T cells has been suggested in a mouse EAE model. However, the nature of antigens that can be presented by MR1 to this invariant T cell subset remained largely unclear. An article in this issue of the European Journal of Immunology presents strong indications that derivatives of ,-mannosyl ceramide (,-ManCer), i.e. glycolipids, can serve as ligands for MR1-restricted invariant T cells. In addition to that, the structure of the ,-ManCer sphingosine chain influences the Th1-Th2 polarization of the cytokine response. These important new findings will foster further research on the identity of physiological ligands for MR1-restricted T cells and on their relation with immunoregulation. See accompanying article: http://dx.doi.org/10.1002/eji.200636689 [source] Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolismEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Jens Schümann Abstract Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme ,-galactosidase (,Gal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in ,Gal,/, and NPC2,/, mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders. [source] Rapid and reliable generation of invariant natural killer T-cell lines in vitroIMMUNOLOGY, Issue 3 2009Asako Chiba Summary Several tools have proved useful in the study of invariant natural killer T (iNKT) cells, including CD1d-deficient mice, J,281-deficient mice, synthetic lipid antigens and antigen-loaded CD1d tetramers. However, the generation and examination of long-term primary murine iNKT cell lines in vitro has been challenging. Here, we show the rapid generation of iNKT cell lines from splenic iNKT cells of V,14 T-cell receptor (TCR) transgenic (Tg) mice. These purified iNKT cells were stimulated by bone marrow-derived dendritic cells (BMDCs) loaded with ,-galactosylceramide (,GalCer) and cultured with interleukin (IL)-2 and IL-7. iNKT cells proliferated dramatically, and the cell number exhibited a 100-fold increase within 2 weeks and a 105 -fold increase in 8 weeks after repeated stimulation with ,GalCer. The iNKT cell lines consisted of iNKT cells expressing V, chains including V,8.1/8.2, V,14, V,10, V,6 and V,7, and responded to stimulation with ,GalCer presented both by BMDCs and by plate-bound CD1d. In addition, the iNKT cell lines produced interferon (IFN)-, when activated by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide (ODN)-stimulated BMDCs. Further, we show that iNKT cell lines produced cytokines in response to microbial antigens. In summary, high-yield iNKT cell lines were generated very rapidly and robustly expanded, and these iNKT cells responded to both TCR and cytokine stimulation in vitro. Given the desire to study primary iNKT cells for many purposes, these iNKT cell lines should provide an important tool for the study of iNKT cell subsets, antigen and TCR specificity, activation, inactivation and effector functions. [source] Serum lipids regulate dendritic cell CD1 expression and functionIMMUNOLOGY, Issue 3 2008David S. Leslie Summary Dendritic cells (DCs) are highly potent antigen-presenting cells (APCs) and play a vital role in stimulating naïve T cells. Treatment of human blood monocytes with the cytokines granulocyte,macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 stimulates them to develop into immature dendritic cells (iDCs) in vitro. DCs generated by this pathway have a high capacity to prime and activate resting T cells and prominently express CD1 antigen-presenting molecules on the cell surface. The presence of human serum during the differentiation of iDCs from monocytes inhibits the expression of CD1a, CD1b and CD1c, but not CD1d. Correspondingly, T cells that are restricted by CD1c showed poor responses to DCs that were generated in the presence of human serum, while the responses of CD1d-restricted T cells were enhanced. We chemically fractionated human serum to isolate the bioactive factors that modulate surface expression of CD1 proteins during monocyte to DC differentiation. The human serum components that affected CD1 expression partitioned with polar organic soluble fractions. Lysophosphatidic acid and cardiolipin were identified as lipids present in normal human serum that potently modulate CD1 expression. Control of CD1 expression was mediated at the level of gene transcription and correlated with activation of the peroxisome proliferator-activated receptor (PPAR) nuclear hormone receptors. These findings indicate that the ability of human DCs to present lipid antigens to T cells through expression of CD1 molecules is sensitively regulated by lysophosphatidic acid and cardiolipin in serum, which are ligands that can activate PPAR transcription factors. [source] Cell wall-associated alpha-glucan is instrumental for Mycobacterium tuberculosis to block CD1 molecule expression and disable the function of dendritic cell derived from infected monocyteCELLULAR MICROBIOLOGY, Issue 8 2007Maria Cristina Gagliardi Summary We previously described an escape mechanism exploited by Mycobacterium tuberculosis (Mtb) to prevent the generation of fully competent dendritic cells (DC). We have now tested the effect of isolated mycobacterial components on human monocyte differentiation into DC and demonstrated that cell wall (CW)-associated alpha-glucan induces monocytes to differentiate into DC (Glu-MoDC) with the same altered phenotype and functional behaviour of DC derived from Mtb-infected monocytes (Mt-MoDC). In fact, Glu-MoDC lack CD1 molecule expression, fail to upregulate CD80 and produce IL-10 but not IL-12. We also showed that Glu-MoDC are not able to prime effector T cells or present lipid antigens to CD1-restricted T-cell clones. Thus, we propose a mechanism of Mtb,monocyte interaction mediated by CW-associated alpha-glucan, which allows the bacterium to evade both innate and acquired immune responses. [source] | ||||||||||