Determining the genetic control of dendritic cell subsets

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Dendritic cells, or DCs, were first described by the Nobel laureate, Dr. Ralph Steinman, over thirty years ago. DCs are white blood cells which play contrasting roles in the immune response. In the absence of infection they tone down the immune response, while in the presence of infection they are the most potent cell type for inducing an immune response.**Since their first description, multiple dendritic subsets have been identified, each bearing unique properties and contributing to different aspects of the immune response. In particular, two main resident conventional DCs are found in the spleen, which are recognized by their reciprocal expression of two proteins, namely CD8a and CD11b. Of interest, mice present with a greater proportion of CD11b+ DC than CD8a+ DC in the spleen. To understand the bias in favor of the CD11b+ DC subset, the ontogeny of DC has been investigated. It is now clear that both CD8a+ and CD11b+ DC subsets originate from cells in the bone marrow. A common cellular precursor has also been identified. Still, the reason for this imbalance in favor of the CD11b+ cDC subset remains to be elucidated.**This research program aims to address this biological question by undertaking an unbiased genetic linkage approach to unravel genes linked to the higher proportion of CD11b+ DC. By investigating the regulation of DC subset variations in inbred strain of mice, for which the genetic code has been established, we will identify a limited set of genes potentially regulating the ratio of CD8a+ to CD11b+ cDC subset. The contribution of these genes will be validated in both in vitro and in vivo model systems. In addition, by exploiting a novel reporter mouse model, we will refine the in vivo differentiation route of cDC subsets. Together, this work will improve our understanding of the genetic, molecular and cellular parameters involved in the differentiation and the homeostatic regulation of the two main cDC subsets, namely CD8a+ to CD11b+ cDCs. In addition, this research program will contribute to the training of at least four highly qualified personnel, namely two graduate students and two undergraduate students.