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TGF-ß1 Prevents the Noncognate Maturation of Human Dendritic Langerhans Cells¹

Frederic Geissmann^2,*,, Patrick Revy, Armelle Regnault^§, Yves Lepelletier^*, Michel Dy^*, Nicole Brousse, Sebastian Amigorena^§, Olivier Hermine^* and Anne Durandy

^* Unité de Recherche Associée 1461, Centre National de la Recherche Scientifique, Pathology Department, and Institut National de la Santé et de la Recherche Médicale, Unité 429, Hopital Necker-Enfants Malades, Faculté Necker, Université Paris-V René-Descartes, Paris, France; and ^§ Institut National de la Santé et de la Recherche Médicale, Contrat Jeune Formation 95–01, Institut Curie, Section Recherche, Paris, France

TGF-ß1 is critical for differentiation of epithelial-associated dendritic Langerhans cells (LC). In accordance with the characteristics of in vivo LC, we show that LC obtained from human monocytes in vitro in the presence of TGF-ß1 1) express almost exclusively intracellular class II Ags, low CD80, and no CD83 and CD86 Ags and 2) down-regulate TNF-RI (p55) and do not produce IL-10 after stimulation, in contrast to dermal dendritic cells and monocyte-derived dendritic cells. Surprisingly, while LC exhibit E-cadherin down-regulation upon exposure to TNF- and IL-1, TGF-ß1 prevents the final LC maturation in response to TNF-, IL-1, and LPS with respect to Class II CD80, CD86, and CD83 Ag expression, loss of FITC-dextran uptake, production of IL-12, and Ag presentation. In sharp contrast, CD40 ligand cognate signal induces full maturation of LC and is not inhibited by TGF-ß1. The presence of emigrated immature LCs in human reactive skin-draining lymph nodes provides in vivo evidence that LC migration and final maturation may be differentially regulated.

Therefore, due to the effects of TGF-ß1, inflammatory stimuli may not be sufficient to induce full maturation of LC, thus avoiding potentially harmful immune responses. We conclude that TGF-ß1 appears to be responsible for both the acquisition of LC phenotype, cytokine production pattern, and prevention of noncognate maturation.