Certain types of dendritic cells (DCs) appear in inflammatory lesions of various etiologies, whereas other DCs, e.g., Langerhans cells (LCs), populate peripheral organs constitutively. Until now, the molecular mechanism behind such differential behavior has not been elucidated. Here, we show that CD1a+ LC precursors respond selectively and specifically to the CC chemokine macrophage inflammatory protein (MIP)-3α. In contrast, CD14+ precursors of DC and monocytes are not attracted by MIP-3α. LCs lose the migratory responsiveness to MIP-3α during their maturation, and non-LC DCs do not acquire MIP-3α sensitivity. The notion that MIP-3α may be responsible for selective LC recruitment into the epidermis is further supported by the following observations: (a) MIP-3α is expressed by keratinocytes and venular endothelial cells in clinically normal appearing human skin; (b) LCs express CC chemokine receptor (CCR)6, the sole MIP-3α receptor both in situ and in vitro; and (c) non-LC DCs that are not found in normal epidermis lack CCR6. The mature forms of LCs and non-LC DCs display comparable sensitivity for MIP-3β, a CCR7 ligand, suggesting that DC subtype–specific chemokine responses are restricted to the committed precursor stage. Although LC precursors express primarily CCR6, non-LC DC precursors display a broad chemokine receptor repertoire. These findings reflect a scenario where the differential expression of chemokine receptors by two different subpopulations of DCs determines their functional behavior. One type, the LC, responds to MIP-3α and enters skin to screen the epidermis constitutively, whereas the other type, the “inflammatory” DC, migrates in response to a wide array of different chemokines and is involved in the amplification and modulation of the inflammatory tissue response.

Peroxisome proliferator‐activated receptor γ  (PPARγ ), a member of the nuclear receptor superfamily, has recently been described as a modulator of macrophage functions and as an inhibitor of T cell proliferation. Here, we investigated the role of PPARγ  in dendritic cells (DC), the most potent antigen‐presenting cells. We showed that PPARγ  is highly expressed in immature human monocyte‐derived DC (MDDC) and that it may affect the immunostimulatory function of MDDC stimulated with lipopolysaccharide (LPS) or via CD40 ligand (CD40L). We found that the synthetic PPARγ  agonist rosiglitazone (as well as pioglitazone and troglitazone) significantly increases on LPS‐ and CD40L‐activated MDDC, the surface expression of CD36 (by 184% and 104%, respectively) and CD86 (by 54% and 48%), whereas it reduces the synthesis of CD80 (by 42% and 42%). Moreover, activation of PPARγ  resulted in a dramatic decreased secretion of the Th1‐promoting factor IL‐12 in LPS‐ and CD40L‐stimulated cells (by 47% and 62%), while the production of IL‐1β , TNF‐α , IL‐6 and IL‐10 was unaffected. Finally, PPARγ  ligands down‐modulate the synthesis of IFN‐γ ‐inducible protein‐10 (recently termed as CXCL10) and RANTES (CCL5), both chemokines involved in the recruitment of Th1 lymphocytes (by 49% and 30%), but not the levels of the Th2 cell‐attracting chemokines,macrophage‐derived chemokine (CCL22) and thymus and activation regulated chemokine (CCL17), in mature MDDC. Taken together, our data suggest that activation of PPARγ  in human DC may have an impact in the orientation of primary and secondary immune responses by favoring type 2 responses.

The polarization of the immune response toward a Th2 or a Th1 profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such as CD80 and CD86 expressed by DCs, the polarizing cytokine environment during DC-T-cell interaction, and also the nature of the antigen are critical in the orientation of the immune response. In this study, the effect of the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, on these different parameters was evaluated comparatively on monocyte-derived DCs obtained from healthy donors, from pollen-sensitive patients, or from patients sensitive to Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust mite-sensitive patients. This was also associated with a higher capacity to induce T-cell proliferation, a rapid increase in the production of proinflammatory cytokines, tumor necrosis factor-␣ and interleukin (