Immune role of CD14+ & CD14- human skin dendritic cells

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DESCRIPTION (provided by applicant): Peripheral tissue-resident dendritic cells (DCs) are professional antigen (Ag) presenting cells (APCs) that initiate primary T cell immune responses. To achieve this, they: i) take up and process Ags; ii) migrate from periphery to draining lymph nodes; and iii) prime naive T cells. Besides their potent T cell stimulatory function, peripheral tissue resident-DCs play a key role in maintenance of peripheral tolerance in steady-state conditions. A crucial step for initiation of immunity or tolerance is the priming and biasing of naive CD4 T cells into T helper (Th) 1 cells (cellular immune response), Th2 cells (humoral immunity) or regulatory T cells (TR) (tolerance). Activation and biasing of naive CD4 T cells by DCs are determined mainly by: i) the characteristics of the DC-T cell synapse, and ii) the pattern of cytokines secreted by DCs during DC-T cell contact. The level of T cell stimulatory molecules on the DC surface and the pattern DC cytokines are influenced greatly by the characteristics of the stimuli (danger signals) during activation of DCs in peripheral tissues. As examples, activation of skin DCs by dinitrocholorobenzene (DNCB) induces a prevalent Th1 response, DC-activation by FITC generates a Th2-biased response and skin UV-B irradiation favors tolerance. Conversely, it is still not clear the nature of the stimuli that trigger steady migration of DCs from periphery in the absence of tissue damage. Moreover, the mechanisms involved in the initiation of T cell responses by peripheral tissue resident DCs have not been analyzed in humans. To address these questions a model of ex-vivo human skin explants that permits to analyze the T cell stimulatory function of different types of skin migratory (smi) DCs and the effect that immunostimulatorv (danger signals) or tolerogenic stimuli may exert on cutaneous DCs would be ideal. We and others have previously identified, based on the expression of the molecule CD14, two populations of skin migratory (smi)DCs: i) smiCD14- DCs, that exhibit phenotype of mature APCs and strong naive T cell stimulatory ability; and ii)smiCD14+ DCs, with a more immature APC phenotype and weak stimulators of naive T cells. In the present We propose to: 1) Compare the immune functions of smiCD14+DCs and smiCD14-DCs spontaneously mobilized from human skin explants, and 2) Determine activation and function of smiCD14+DCs and smiCD14-DCs from epidermal/dermal explants exposed to DNCB (a Th1-biasing sensitizer), FITC (a Th2-biasing sensitizer) or UV-B irradiation (TR-driving stimulus).