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HLA-DR-Mediated Apoptosis Susceptibility Discriminates Differentiation Stages of Dendritic/Monocytic APC¹

Nicolas Bertho^*, Bernard Drénou^*, Béatrice Laupeze^*, Claudine Le Berre, Laurence Amiot^*, Jean-Marc Grosset^*, Olivier Fardel, Dominique Charron^§, Nuala Mooney^2,§ and Renée Fauchet^*

^* Laboratoire Universitaire d’Hématologie et de Biologie des Cellules Sanguines, Institut National de la Santé et de la Recherche Médicale CRI 9606-UPRES EA 22-33, Rennes, France; Etablissement de Transfusion Sanguine de Bretagne, Rennes, France; Institut National de la Santé et de la Recherche Médicale U456 Université de Rennes I, Rennes, France; and ^§ Institut National de la Santé et de la Recherche Médicale U396 Institut des Cordeliers, Paris, France

Professional APC are characterized by their ability to present peptide via HLA class II in the presence of costimulatory molecules (CD40, CD80, and CD86). The efficiency of Ag presentation can be classed as follows: mature dendritic cells (DC) are most efficient, immature DC and macrophages are intermediate, and monocytes are considered poor APC. There is a large body of evidence demonstrating that HLA-DR transmits signals in the APC. In this study, we have addressed the question of the outcome of HLA-DR signals on APC of the monocyte/DC lineages throughout their differentiation from immature to mature APC. DC were generated from both monocytes and CD34⁺ cells of the same individual, macrophages were differentiated from monocytes. Immunophenotypical analysis clearly distinguished these populations. HLA-DR-mediated signals led to marked apoptosis in mature DC of either CD34 or monocytic origin. Significantly less apoptosis was observed in immature DC of either origin. Nonetheless, even immature DC were more susceptible to HLA-DR-mediated apoptosis than macrophages, whereas monocytes were resistant to HLA-DR-mediated apoptosis. The mechanism of HLA-DR-mediated apoptosis was independent of caspase activation. Taken together, these data lead to the notion that signals generated via HLA-DR lead to the demise of mature professional APC, thereby providing a means of limiting the immune response.