Uptake of apoptotic dendritic cells by viable dendritic cells: a novel mechanism of inducing immune tolerance (48.7)

Abstract

Abstract Dendritic cells (DCs) are professional antigen-presenting cells, which can be affected by the death of other cells in close proximity. Spontaneous DC apoptosis has been observed in patients with sepsis and breast cancer. Additionally defects in DC apoptosis have also been associated with development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses are unclear. Here we show that apoptotic DCs can mediate induction of immune tolerance by converting immature DCs into tolerogenic DCs. The uptake of apoptotic DCs by viable DCs prevents LPS-induced activation and T-cell proliferation, and also results in the upregulation of TGF-beta2 gene expression and TGF-beta1 secretion, which mediates differentiation of naïve T cells into regulatory T cells (Tregs). Additionally, delivery of apoptotic DCs prevents LPS-induced DC maturation and migration to lymph nodes in mice. Moreover, intranasal delivery of apoptotic DCs to LPS-inflamed lungs results in rapid resolution of inflammation along with production of TGF-beta1 and expansion of Tregs. Delivery of apoptotic DCs followed by immunization with ovalbumin (OVA) in Complete Freund's Adjuvant (CFA) resulted in generation of OVA-specific Tregs in wild-type mice and expansion of Tregs in T-cell receptor transgenic (OT-II) mice. Taken together, our findings identify apoptotic DCs as potent inducers of immunological tolerance.