Combined TLR/CD40-Agonist Induced CD8+ T Cell Memory

Kedl, Ross

Abstract

Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. This combined TLR/CD40 immunization generates CD8+ T cell responses even in CD4-depleted or CD4-deficient hosts. We have substantiated our previous hypothesis and have further observations which suggest an involvement of CD27 in regulating that activity of the transcription factor Blimp-1, the levels of which subsequently control the presence or absence of CD8+ T cell memory. Based on these results, this proposal will test the hypothesis that protective, CD4-independent CD8+ T cell immune memory requires a shift in the balance of the Blimp-1/Bcl-6 regulatory axis within CD8+ memory T cells (6, 7), a shift requiring the participation of the TNF receptor superfamily members CD27 and/or OX40 via CD70/OX40L expressing DCs. We will examine whether combined TLR/CD40-agonist immunization elicits CD4-independent CD8+ T cell memory by engaging the CD27/OX40 TNF receptors on antigen specific T cells, leading to the suppression of Blimp-1 expression in the T cell via Bcl-6 or an as yet undetermined molecular mechanism.

Public Health Relevance

The need for effective therapeutic vaccines has never been greater and yet none currently exist, at least with respect to therapeutic intervention in the majority of infectious diseases and cancers. The need is great for vaccines against chronic infectious agents such as HIV, malaria, TB and HCV. What is needed is a noninfectious vaccine capable of producing the kind of immunity that can be useful against these infectious agents, especially in patients whose immune systems are already compromised such as those infected with HIV. After a single immunization, our vaccine produces the most potent cellular immune response yet observed of any non-infectious vaccine. As a testament to its potency, our vaccine produces robust immunity capable of protecting against infectious challenge, even in mice whose immune system is compromised in the same way as an HIV infected patient?s. The studies proposed in this renewal application will explore the reasons why our vaccine is so efficacious so we can use that knowledge to further manipulate immune responses to our advantage.