Immunological tolerance to self is essential in the prevention of autoimmune disease. Although central tolerance is remarkably efficient, potentially autoaggressive T cells can reach the periphery. Peripheral mechanisms of tolerance induction are therefore required to protect peripheral tissues from autoimmune attack. The two main types of dendritic cells (DC) are conventional DC (cDC) and plasmacytoid DC (pDC), both derived from the hematopoietic lineage. The prevailing model for peripheral tolerance involves the cross-presentation of tissue antigens (Ag) by quiescent cDC. The exposure of cDC to selected inflammatory stimuli can change the outcome of the immune response from tolerance to immunity. In contrast to cDC, pDC were initially believed to be involved in innate immune responses via the secretion of type I interferons following viral or bacterial infections. However, recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. These models involving cDC and/or pDC limit however the presentation of particular Ags to the lymph nodes draining the tissues in which the Ag is expressed. An alternative mechanism, involving non-hematopoietic lymph node stromal cells, has recently emerged. In this mechanism, the lymph node stromal cells express various tissue self-Ag and could thus contribute to peripheral T cell tolerance. This grant application will investigate whether non-hematopoietic stromal cells can present tissue self-Ag in inflammatory situations in vivo, and whether it has a impact on T cell responses during the development of diseases. Overall, we will investigate the respective contribution of hematopoietic and non-hematopoietic cellular compartments in the maintenance of peripheral T cell tolerance and prevention from disease.