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Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Abstract

The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.

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Acknowledgements

We thank D. Williams and T. Gillis (National Hansen's Disease Programs) for use of their unpublished data on expression of ML1966 mRNA, W. Chung for technical assistance and S. Smale for critical comments on the manuscript and scientific discussion. This work was supported in part by grants from the National Institutes of Health (AI07126, AI22553 and AI47866) and the World Health Organization (IMMLEP).

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Correspondence to Robert L. Modlin.

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The authors declare no competing financial interests.

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Figure 1: TLR2 and TLR2-TLR1 mediate the response to M. leprae and M. leprae 19-kD and 33-kD lipopeptides.
Figure 2: Cytokine profiles influence TLR2-TLR1 activation of monocyte and monocyte-derived dendritic cells.
Figure 3: Effect of cytokines on TLR2 and TLR1 expression on monocytes and monocyte-derived dendritic cells.
Figure 4: TLR2 and TLR1 expression on peripheral monocytes, and activation of monocytes and monocyte-derived dendritic cells in leprosy patients.
Figure 5: Expression of TLR2 and TLR1 in leprosy patients.
Figure 6: Phenotype of cells expressing TLR2 in T-lep lesions.