At the temperature of its flea vector (∼ 20–30 C), the causative agent of plague, Yersinia pestis, expresses a profile of genes distinct from those expressed in a mammalian host (37 C). When dendritic cells (DC) are exposed to Y. pestis grown at 26 C (Y. pestis-26), they secrete copious amounts of IL-12p40 homodimer (IL-12 (p40) 2). In contrast, when DCs are exposed to Y. pestis grown at 37 C (Y. pestis-37), they transcribe very little IL-12p40, which is secreted as IL-12p40 monomer (IL-12p40). Y. pestis-26 also induces migration of DCs to the homeostatic chemokine CCL19, whereas Y. pestis-37 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 results in the production of a hexa-acylated lipid A, also seen in Y. pestis-26, rather than tetra-acylated lipid A normally seen in Y. pestis-37. The LpxL-expressing Y. pestis-37 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. 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.