Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells

Hunger, Robert E.; Sieling, Peter A.; Ochoa, Martín; Sugaya, Makoto; Burdick, Anne E.; Rea, Thomas H.; Brennan, Patrick J.; Belisle, John T.; Blauvelt, Andrew; Porcelli, Steven A.; Modlin, Robert L.

doi:10.1172/jci19655

Cited by 129 publications

(103 citation statements)

References 43 publications

(21 reference statements)

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“…Moreover, Langerin and CD1a share a common intracellular pathway in LCs, traveling through identical intracellular compartments (Salamero et al, 2001;Mc Dermott et al, 2002). Hunger et al (2004) have reported that nonpeptide antigens of Mycobacterium leprae are presented by freshly isolated epidermal LCs to T cell clones derived from the cells of leprosy patients, in a CD1a-restricted Langerin-dependent manner. BGs may therefore correspond to a specialized membrane domain of the ERC, devoted to the loading of CD1a with glycolipids internalized and routed to the BGs by Langerin, as suggested previously by Mc Dermott et al (2002).…”

Section: Discussionmentioning

confidence: 99%

Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

Uzan-Gafsou

Bausinger²,

Proamer³

et al. 2007

MBoC

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The extent to which Rab GTPases, Rab-interacting proteins, and cargo molecules cooperate in the dynamic organization of membrane architecture remains to be clarified. Langerin, a recycling protein accumulating in the Rab11-positive compartments of Langerhans cells, induces the formation of Birbeck granules (BGs), which are membrane subdomains of the endosomal recycling network. We investigated the role of Rab11A and two members of the Rab11 family of interacting proteins, Rip11 and RCP, in Langerin traffic and the biogenesis of BGs. The overexpression of a dominant-negative Rab11A mutant or Rab11A depletion strongly influenced Langerin traffic and stability and the formation of BGs, whereas modulation of other Rab proteins involved in dynamic regulation of the endocytic-recycling pathway had no effect. Impairment of Rab11A function led to a missorting of Langerin to lysosomal compartments, but inhibition of Langerin degradation by chloroquine did not restore the formation of BGs. Loss of RCP, but not of Rip11, also had a modest, but reproducible effect on Langerin stability and BG biogenesis, pointing to a role for Rab11A-RCP complexes in these events. Our results show that Rab11A and Langerin are required for BG biogenesis, and they illustrate the role played by a Rab GTPase in the formation of a specialized subcompartment within the endocytic-recycling system.

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Section: Discussionmentioning

confidence: 99%

Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

Uzan-Gafsou

Bausinger²,

Proamer³

et al. 2007

MBoC

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“…PIM and LAM may represent special cases in which a single lipid can activate T cells indirectly through TLRs and also directly through TCRs. However, further studies of LAM will be needed to determine whether the dominant mechanism of T activation involves synthesis of new CD1 proteins or presentation of LAM bound within the CD1b groove (4,18). These in vitro studies of human monocytes now suggest that the simultaneous delivery of both types of activating signals by intact bacteria or sloughed lipids could promote the efficient uptake and presentation of foreign lipids by those myeloid precursors of DCs that encounter pathogens at sites of infection in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…For example, myeloid dendritic cells use the mannose receptor (CD206) and Langerhans cells use langerin (CD207) to deliver exogenous lipid Ags to endosomes (17,18), where saposin lipidtransfer proteins and a low pH environment promote binding of lipid Ags to CD1 proteins (19 -22). Such endosomal loading pathways are necessary for efficient T cell activation by most or all known bacterial lipid Ags, including mycolic acid, lipoarabinomannan (LAM), glucose monomycolate (GMM), mannosyl phosphomycoketides, and didehydroxymycobactins (DDM) (1,4,(23)(24)(25).…”

mentioning

confidence: 99%

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

Roura-Mir

Wang

Cheng

et al. 2005

The Journal of Immunology

115

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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“…Lectin-binding receptors including the mannose receptor are required for efficient endocytosis of glycoprotein (33) and glycolipid (34,35) Ags for their presentation to T cells. In the present study, it was not possible to differentiate whether the carbohydrate moiety was required for efficient Ag uptake/processing or if it was directly involved in T cell recognition.…”

Section: Discussionmentioning

confidence: 99%

Conserved Mycobacterial Lipoglycoproteins Activate TLR2 but Also Require Glycosylation for MHC Class II-Restricted T Cell Activation

Sieling¹,

Hill

Dobos

et al. 2008

The Journal of Immunology

Self Cite

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CD4+ T cell clones derived from a leprosy lesion and patient blood were used to monitor the isolation and identification of an Ag associated with the self-limited form of the disease. Biochemical purification and genetic analysis identified the T cell Ag as a conserved mycobacterial lipoglycoprotein LprG. LprG-mediated activation of CD4+ T cells required specific MHC class II restriction molecules and intracellular processing. Although LprG activated TLR2, this alone was not sufficient to stimulate or inhibit T cell activation. A striking finding was that the carbohydrate moieties of LprG were required for optimal T cell activation, because recombinant LprG produced in Escherichia coli, or recombinant LprG produced in Mycobacterium smegmatis and digested by α-mannosidase, did not activate T cells. This study demonstrates that the universe of bacterial T cell Ags includes lipoglycoproteins, which act as TLR2 ligands but also require glycosylation for MHC class II-restricted T cell activation in vivo.

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Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells

Cited by 129 publications

References 43 publications

Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

Conserved Mycobacterial Lipoglycoproteins Activate TLR2 but Also Require Glycosylation for MHC Class II-Restricted T Cell Activation

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