The Journal of Experimental Medicine
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Published 20 October 2003. doi:10.1084/jem.20030335
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© Rockefeller University Press, 0022-1007/2003/10/1253 $5.00
The Journal of Experimental Medicine, Volume 198, Number 8, 1253-1263

Lipopolysaccharide or Whole Bacteria Block the Conversion of Inflammatory Monocytes into Dendritic Cells In Vivo

Gianluca Rotta1, Emmerson W. Edwards2, Sabina Sangaletti3, Clare Bennett4, Simona Ronzoni1, Mario P. Colombo3, Ralph M. Steinman5, Gwendalyn J. Randolph2 and Maria Rescigno1

1 Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
2 Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mt. Sinai School of Medicine, New York, NY 10029
3 Immunotherapy and Gene Therapy Unit, Istituto Nazionale dei Tumori, 20133 Milan, Italy
4 Department of Cell Biology and Histology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
5 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021

Address correspondence to Maria Rescigno, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milano, Italy. Phone: 39-02-57489866; Fax: 39-02-57489851; email: mrescigno{at}lar.ieo.it

Monocytes can develop into dendritic cells (DCs) that migrate to lymph nodes (LNs) and present antigens to T cells. However, we find that this differentiation is blocked when monocytes accumulate subcutaneously in response to bacteria or lipopolysaccharide (LPS). The inhibition of DC differentiation is mediated by the bacteria and in conjunction with inflammatory cells recruited at the site of injection. Inhibition of migratory DC development was reversed in Toll-like receptor (TLR)4-mutated mice when LPS, but not whole bacteria, was injected, suggesting that TLR4 is one but not the only mediator of the inhibition. The block imposed by bacteria was partly relieved by the absence of interleukin (IL)-12 p40, but not by individual absence of several cytokines involved in DC differentiation or in inflammation, i.e., IL-6, IL-10, IL-12 p35, and interferon {gamma}. Consistent with the inability of monocytes to yield migrating DCs, and the finding that other DCs had limited access to particulate or bacterial antigens, these antigens were weakly presented to T cells in the draining LN. These results illustrate that bacteria-associated signals can have a negative regulatory role on adaptive immunity and that local innate responses for containment of infectious bacteria can at least initially supersede development of adaptive responses.

Key Words: Salmonella typhimurium • migration • inflammation • innate immunity • adaptive immunity


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