The impact of antigen processing on CD8+ t cell memory inflation

Thesis

T cell "memory inflation" is the sustained induction of effector memory cells that home to peripheral tissues and retain their functionality. Defining the mechanisms that drive these non-classical memory responses may contribute towards the development of novel prophylactic or therapeutic vaccines. A model of memory inflation based on responses to β-galactosidase delivered by a non-replicating adenoviral vector provides a robust tool for investigating the underlying mechanisms. This work has shown that these responses are not dependent upon the human cytomegalovirus (HCMV) promoter within the model, this being the only part of the model that is CMV-derived. This model has been used to test the hypothesis that bypassing antigen processing would result in inflationary memory responses to CD8⁺ T cell epitopes that are not normally the targets of such responses. When the β-gal_497-504 restricted epitope (ICPMYARV) was expressed as a minigene in a recombinant adenovirus vector, inflationary CD8⁺ T cell responses were induced, instead of the classical responses obtained with full-length β-galactosidase. Similar results were obtained with the M45_985-993 (HGIRNASFI) epitope from the mouse cytomegalovirus M45 protein. These data demonstrate that the polypeptide context of a CD8⁺ T cell epitope may determine whether classical or inflating memory responses are induced. This could be relevant to the design of recombinant antigens in adenoviral vectors, which have emerging therapeutic and prophylactic applications.

Authors: Colston, J

• DOI: 10.5287/ora-9r5grbzmp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Keywords: CD8+ T cell memory inflation
• Subjects: Cellular immunity