Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

Abstract

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.

Structural Determination and Toll-like Receptor 2-dependent Proinflammatory Activity of Dimycolyl-diarabino-glycerol from Mycobacterium marinum

“…Although this result has to be confirmed experimentally, it suggests that DMAG could also modulate the effectiveness of lipidic antigen presentation to natural killer T cells. In agreement with our results, Roura-Mir et al (76) previously demonstrated that the mycobacterial cell wall lipids of M. tuberculosis that activate human monocytes through TLR2 up-regulated CD1a, CD1b, and CD1c gene and protein expression, whereas CD1d transcripts decreased on the first day after exposure to the lipids.…”

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

“…Indeed, TLR-2 and TLR-4 are important to control infection (Reiling et al, 2002) and mycobacterial lipids are known to be ligands for TLRs, triggering production of IL-12 and other factors. As suggested by Roura-Mir et al (2005), mycobacterial cell wall lipids may provide two distinct signals. One signal may lead to the activation of lipid-reactive T cells while the other may act as a lipid adjuvant to activate antigen-presenting cells through TLR-2.…”

Viral danger signals control CD1d de novo synthesis and NKT cell activation

“…Unlike virus infection and viral pathogen-associated patterns, treatment of DC with nonviral TLR ligands (LPS, zymosan) strongly decreased the number of CD1D mRNA transcripts. Others have shown diminished CD1D mRNA expression in monocytes exposed to Mycobacterium tuberculosis lipids [58]. Accordingly, LPS-treated DC produced lower amounts of the CD1d heavy chain (data not shown).…”

“…Others have shown diminished CD1D mRNA expression in monocytes exposed to Mycobacterium tuberculosis lipids [58]. Accordingly, LPS-treated DC produced lower amounts of the CD1d heavy chain (data not shown).…”