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. In the process of investigating our originally funded aims directed toward the role of type I IFN (IFN) in TLR/CD40 vaccination, we made the surprising discovery that the T cell response to any adjuvant containing a TLR-agonist is unexpectedly and completely dependent on IL-27. This is in sharp contrast to immunization with infectious vectors such as vaccinia or Listeria monocytogenes (LM) where the impact of IL-27 is negligible. Our data thus reveal a specific, obligate, and previously unappreciated role for IL-27 in non-infectious, subunit vaccine elicited cellular responses. Given the potency with which our combination adjuvant elicits cellular immunity, the obligate role of IL-27 in the cellular response to combined innate/CD40 vaccination is reason enough for further examination. The additional and unexpected reality that essentially all molecularly defined vaccine adjuvants require the participation of IL-27 for eliciting cellular responses only adds to the importance of the studies proposed in this application. To fully understand the role of IL-27 in vaccine-elicited cellular immunity, we will clarify i) the sites and magnitude of IL-27 production, ii) the required pattern f IL-27R expression, iii) the role of IL-27 elicited STAT1 and STAT3 activation in DCs and T cells, and iv) the mechanisms by which vaccination and infectious processes diverge in their degree of IL-27 dependency.
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 non- infectious 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. In the process of investigating this and other vaccination strategies, we made the surprising discovery that the T cell response to any adjuvant containing an innate receptor agonist (TLRs, RLRs etc.) is unexpectedly and completely dependent on IL-27. This is in sharp contrast to immunization with infectious vectors such as vaccinia or Listeria monocytogenes where the impact of IL-27 is negligible. Thus IL- 27 plays a very different role in the T cell response to defined adjuvants than it does in response to infection. The studies proposed in this application will explore the underlying mechanisms of the IL-27 dependence of vaccine-elicited cellular responses so we can use that knowledge to further manipulate immune responses to our advantage.
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|Burchill, Matthew A; Tamburini, Beth A; Kedl, Ross M (2015) T cells compete by cleaving cell surface CD27 and blocking access to CD70-bearing APCs. Eur J Immunol 45:3140-9|
|Thompson, Elizabeth A; Liang, Frank; Lindgren, Gustaf et al. (2015) Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates. J Immunol 195:1015-24|
|Kedl, Justin D; Kedl, Ross M (2015) How squalene GLAdly helps generate antigen-specific T cells via antigen-carrying neutrophils and IL-18. Eur J Immunol 45:376-9|
|Tamburini, Beth A; Burchill, Matthew A; Kedl, Ross M (2014) Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat Commun 5:3989|
|Pennock, Nathan D; Gapin, Laurent; Kedl, Ross M (2014) IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization. Proc Natl Acad Sci U S A 111:16472-7|
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