Cell death, dendritic cells and downregulation of the immune response

• Main Author: Stuart, Lynda Maria
• Published: University of Edinburgh 2003
• Subjects: 616.079
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.662569

Apoptotic cells are an important source of many autoantigens and the realization that dendritic cells (DCs), the main antigen presenting cell of the adaptive immune system, not only internalise such drying cells but present antigen derived from them had important implications for our understanding of autoimmunity, tumour immunology and anti-viral responses. The aim of this thesis was to explore the likely consequences of clearance of cells dying by constitutive apoptosis by myeloid phagocytes, with particular emphasis on the mechanism and outcome of DC clearance and the implications for autoimmunity. Firstly it will show that DCs generated from murine bone marrow demonstrated many characteristics attributed to DCs in vivo including endocytosis and phagocytosis and mature upon receipt of danger signals such as endotoxin. However, internalisation of apoptotic cells does not augment DC maturation but rather inhibits subsequent responses to LPS, rendering these DCs less efficient than their neighbours at stimulating naïve T cells. These effects do not appear to be due to secretion of inhibitory cytokines such as TGFβ or IL10 and are not dependent on CD36 or β3/5 integrins, receptors thought to be involved in DC internalisation of apoptotic cells. In addition apoptotic cells inhibit LPS driven IL12 production by <i>ex vivo</i> DCs and in mice immunised with apoptotic cells <i>in vivo</i>. Furthermore, macrophages, likely to be found in high numbers in the inflammatory site also inhibit DCs and these inhibitory effects could be further augmented by the presence of apoptotic cells. Taken together these data demonstrate that internalisation of apoptotic cells by myeloid phagocytes modulates the adaptive immune response and suggests that the likely outcome of internalisation of cells dying by constitutive apoptosis will be tolerance rather than autoimmunity.