Yersinia pestis Evades TLR4-dependent Induction of IL-12(p40)2 by Dendritic Cells and Subsequent Cell Migration

• Published in: The Journal of immunology (1950) Vol. 181; no. 8; pp. 5560 - 5567
• Main Authors: Robinson, Richard T, Khader, Shabaana A, Locksley, Richard M, Lien, Egil, Smiley, Stephen T, Cooper, Andrea M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.10.2008
• Subjects: Acetylation; Acyltransferases - genetics; Acyltransferases - immunology; Animals; Cell Movement - genetics; Cell Movement - immunology; Cells, Cultured; Chemokine CCL19 - genetics; Chemokine CCL19 - immunology; Dendritic Cells - immunology; Dendritic Cells - microbiology; Dimerization; Escherichia coli - genetics; Escherichia coli - immunology; Escherichia coli Proteins - genetics; Escherichia coli Proteins - immunology; Gene Expression Regulation, Bacterial - genetics; Gene Expression Regulation, Bacterial - immunology; Hot Temperature; Humans; Insect Vectors - microbiology; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - immunology; Lipid A - genetics; Lipid A - immunology; Mice; Mice, Knockout; Plague - genetics; Plague - immunology; Siphonaptera - microbiology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Yersinia pestis - genetics; Yersinia pestis - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.8.5560

At the temperature of its flea vector (approximately 20-30 degrees C), the causative agent of plague, Yersinia pestis, expresses a profile of genes distinct from those expressed in a mammalian host (37 degrees C). When dendritic cells (DC) are exposed to Y. pestis grown at 26 degrees C (Y. pestis-26 degrees), they secrete copious amounts of IL-12p40 homodimer (IL-12(p40)(2)). In contrast, when DCs are exposed to Y. pestis grown at 37 degrees C (Y. pestis-37 degrees), they transcribe very little IL-12p40, which is secreted as IL-12p40 monomer (IL-12p40). Y. pestis-26 degrees also induces migration of DCs to the homeostatic chemokine CCL19, whereas Y. pestis-37 degrees does not; migratory DCs are positive for IL-12p40 transcription and secrete mostly IL-12(p40)(2); DCs lacking IL-12p40 do not migrate. Expression of acyltransferase LpxL from Escherichia coli in Y. pestis-37 degrees results in the production of a hexa-acylated lipid A, also seen in Y. pestis-26 degrees, rather than tetra-acylated lipid A normally seen in Y. pestis-37 degrees. The LpxL-expressing Y. pestis-37 degrees promotes DC IL-12(p40)(2) production and induction of DC migration. In addition, absence of TLR4 ablates production of IL-12(p40)(2) in DC exposed to Y. pestis-26 degrees. The data demonstrate the molecular pathway by which Y. pestis evades induction of early DC activation as measured by migration and IL-12(p40)(2) production.