Caractérisation immunogénétique des cellules dendritiques non-conventionelles dans un contexte auto-immun
Dendritic cells (DC) play a key role in the immune system by bridging the innate and adaptive immune system using their Antigen Presenting Cell (APC) function. They can be subdivided into several subsets with distinct features, which are involved in either tolerogenic or inflammatory processes. Variations in the in vivo number of those DC subsets have been associated with genetic susceptibility to certain diseases, such as autoimmune diabetes.  However, proving a causal connection from these correlations remains a challenge, as we have not identified the factors involved in the specific regulation of the DC subsets number, limiting our ability to modulate theses phenotypes independently. Thus, we aimed to identify genetic determinants responsible for the specific regulation of DC subset numbers using linkage analysis in mice, to then determine if autoimmune diabetes susceptibility varies following DC subset modulations.  We have shown an increase in pDC number in NOD mice, which is genetically susceptible to autoimmune diabetes. This phenotype is regulated by a dominant locus on proximal chromosome 7, but it not associated with diabetes incidence in congenic mice. In contrast, we also observe an increase in the number of a novel DC subset, termed mcDC, which is regulated by a distal chromosome 2 interval. This locus, termed Idd13, is also associated with diabetes genetic susceptibility, suggesting a vital role of mcDC in disease, possibly through their T cell anergy reversal function.    These results show that DC subsets are regulated by distinct determinants.. Despite the correlation between pDC/mcDC number and autoimmune diabetes susceptibility, our results demonstrate a divergent contribution of DC subsets to pathogenesis. We shall investigate further to refine genetic intervals and identify the candidates genes involved in the regulation of both pDC and mcDC in vivo number.
immunologie Dendritic cells Auto-immunity Genetics Diabetes Immuno-deficiency