CONDITIONAL ABLATION OF DENDRITIC CELLS IN TRANSGENIC MICE

Dendritic cells (DC) are professional Ag-presenting cells that play a major role in T cell-mediated immune responses and in thymocyte differ entiation. To better analyze their physiological importance, we sought to generate transgenic mice presenting a conditional DC deficiency. W e used a strategy based on the cell-specific expression of a suicide g ene. The DC-targeted expression is obtained using HIV regulatory seque nces; indirect evidence has suggested that these sequences control a p referential expression in DC. The suicide gene is the herpes simplex v irus type 1 thymidine kinase (HSV1-TK) which allows conditional ablati on of dividing HSV1-TK-expressing cells by converting nucleoside analo gs such as ganciclovir (GCV) into toxic molecules. We generated transg enic mice expressing an HSV1-TK gene transcribed from HIV regulatory s equences. A low but significant HSV1-TK expression was observed in mat ure DC and DC precursors grown from granulocyte-macrophage colony-stim ulating factor-supplemented bone marrow cultures. These HSV1-TK-expres sing DC precursors are specifically killed by GCV. We next treated tra nsgenic mice with GCV, and obtained a specific ablation of DC in splee n and thymus. Ninety percent of spleen DC could be depleted within a w eek, indicating a turnover rate of approximately 15% per day. Interest ingly, this DC depletion always correlated with a major thymic atrophy and disappearance of CD4+CD8+ thymocytes. This animal model should he lp to assess the physiological role of DC in the immune response and i n thymocyte differentiation. It should also help to appreciate the con sequences of DC dysfunction in pathological situations, such as HIV-in fection or allograft rejection.