TAK1-dependent checkpoint in dendritic cell survival regulates immune homeostasis and function

ABSTRACT: Homeostatic control of dendritic cell (DC) survival is crucial for a productive adaptive immune response, but the molecular mechanism is not well defined. Moreover, how DCs influence homeostasis of the immune system under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report here that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells diminished DC populations, especially the CD8+ and CD103+ DC subsets in the lymphoid and non-lymphoid organs, respectively. This was associated with increased apoptosis of DCs, whereas DC proliferation and differentiation from precursors appeared largely normal. In addition, acute deletion of TAK1 caused DC apoptosis, indicating a direct role of TAK1 in actively maintaining DC survival. TAK1 deficiency impaired activities of the pro-survival NF-kB and AKT pathways but upregulated expression of the pro-apoptotic molecule Bim. Under steady state, loss of TAK1 in DCs resulted in a myeloid proliferative disorder, and altered homeostasis of T cells. In response to antigen stimulation, TAK1-deficient DCs were impaired for T cell priming and regulatory T cell generation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system RNA extracted from three replicate samples of wild-type and Map3k7 (TAK1) knockout dendritic cells was analyzed on Affymetrix gene expression arrays

ORGANISM(S): Mus musculus

SUBMITTER: Geoffrey Neale 

PROVIDER: E-GEOD-34417 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress