Antigen presentation, autoimmune diseases, peripheral T-cell tolerance.
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 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. A first objective of our research is to analyze the impact of the selective loss of Ag presentation function by pDC on immune responses in vivo. Mouse models are used for multiple sclerosis and autoimmune diabetes.
These models, which involved cDC and/or pDC, nevertheless limit 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. A second part of our research investigates whether non-hematopoietic stromal cells can present tissue Ag in inflammatory situations in vivo, and whether this has an impact on T-cell responses during the development of diseases. Overall, we are investigating the respective contribution of hematopoietic and non-hematopoietic cellular compartments to the maintenance of peripheral T-cell tolerance and disease prevention.