Title

Dying the good death: Defining the immune response elicited by apoptotic or necrotic cells

Date of Completion

January 2008

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Apoptotic cells are significantly more immunogenic than necrotic cells, even though both forms are identical in antigenic content. When a combination of apoptotic and necrotic cells are used to immunize, the phenotype conferred by apoptotic cells, i.e., high immunogenicity, is dominant. However, necrotic cells are not immuno-suppressive or tolerogenic. Apoptotic and necrotic cells are taken up by antigen presenting cells in an equivalent manner. The priming of naïve T cell response is also equivalent. However, the CD8 T cells elicited by apoptotic cells expand, accumulate and express effector function, while those primed by the necrotic cells do not. This dichotomy does not extend to CD4 cells. Apoptotic and necrotic cells elicit equivalent CD4 priming, accumulation and function. The deficit in CD8 function elicited by necrotic cells can be overcome to varying degrees by anti-CD40 antibody and ligands for TLR4 and TLR9; conversely, the immunogenicity of apoptotic cells can be abrogated by blocking anti-CD 154 antibody. Our results indicate that immunization with apoptotic cells leads to engagement of CD40 on antigen presenting cells; this is essential for their ability to elicit mature functional CD8+ cells. The necrotic cells fail to engage CD40, and this failure is the basis of their lack of immunogenicity. These differences have consequences for understanding of mechanisms of cross-presentation and for efforts towards immunotherapy of cancers and autoimmune pathologies. ^