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. Not only is the primary immune response to this vaccination robust, it also forms long lived, CD8+ T cell memory that can protect against future infectious challenge even in the absence of CD4+ T cells. This has been recently verified in non-human primates, where the vaccine produced responses exponentially stronger than responses to typical viral vectors. Given the potency and clinical potential for this vaccine adjuvant platform, it is critical that we understand its molecular and cellular mechanistic underpinnings. We made the discovery that T cell responses to adjuvanted subunit vaccinations were unexpectedly and completely dependent on the cytokines IL-27 and IL-15. This was surprising because the T cell response to an infectious challenge proceeds unabated, and can even be elevated (for IL-27 deficiency), in the absence of these cytokines. More recently, we have identified the expression of the transcription factor IRF4 as a major result of IL-27/15 signaling during vaccination. IRF4 is well documented to facilitate aerobic glycosylation as the source of energy and biomass generation for T cells during the primary immune response. However, we found that T cells responding to vaccination almost exclusively utilized mitochondrial respiration, a metabolism that is supposed to be used only by nave and memory T cells and not cells undergoing the dramatic proliferative burst of the primary response. Thus, IRF4 appears to be facilitating very different kinds of metabolic programs in a T cell depending on whether or not it has been encountered the inflammatory environment of a subunit vaccine or of an infection. These and other observations make us conclude that the rules behind robust subunit vaccine-elicited immunity appear to be substantially different than those guiding infectious responses. This proposal will use cutting edge methods and approaches to fully understand the nature of this difference and will test i) how IL-27 and IL-15 influence downstream transcription factor networks, ii) how these transcriptional elements are tied into vaccine- vs. infection-driven programs of T cell activation and expansion, and iii) how the earliest T-DC interactions might influence both transcription factor expression and downstream influence on metabolic programming of the primary CD8+ T cell response.

Public Health Relevance

After a single immunization, our vaccine produces the most potent cellular immune response yet observed of any non-infectious vaccine, capable of protecting against infectious challenge even in mice whose immune system is compromised. In the process of investigating this and other vaccination strategies, we made the surprising discovery that the T cell response to our vaccine requires the participation of two soluble factors (IL- 27 and IL-15) that appear to be required for the cell to meet the metabolic demands of the primary immune response. Surprisingly, this form of metabolism was mitochondrial respiration, a metabolism that is supposed to be used only by nave and memory T cells and not cells undergoing the dramatic proliferative burst of the primary response. In contrast, and consistent with published data, T cell responses to infections use glycolysis, not mitochondrial respiration, as their dominant source for energy and biomass generation. These differences in metabolism were related to the expression of the same transcription factor, IRF4. Thus, in response to one form of antigen challenge (vaccination), IRF4 facilitates one form of metabolism (mitochondrial respiration) and in response to another form of antigen challenge (infection), the same factor facilitates a completely different metabolism (aerobic glycolysis). These and other observations from our lab are only consistent with the conclusion that subunit vaccine-elicited responses are very different than those governing responses to infections. The studies proposed in this application will explore what mediates these important differences between the two immune challenges. We believe the information gained will be important for the eventual development of better vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066121-14
Application #
10083688
Study Section
Immunity and Host Defense (IHD)
Program Officer
Singleton, Kentner L
Project Start
2007-01-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kilgore, Augustus M; Welsh, Seth; Cheney, Elizabeth E et al. (2018) IL-27p28 Production by XCR1+ Dendritic Cells and Monocytes Effectively Predicts Adjuvant-Elicited CD8+ T Cell Responses. Immunohorizons 2:1-11
Klarquist, Jared; Chitrakar, Alisha; Pennock, Nathan D et al. (2018) Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis. Sci Immunol 3:
Homann, Dirk; Kedl, Ross M (2018) Dimensions of immunologic memory. Immunol Rev 283:5-6
Kedl, Ross M; White, Jason T (2018) Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity? Nat Rev Immunol 18:1
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2017) Corrigendum: Spontaneous partial loss of the OT-I transgene. Nat Immunol 18:951
White, Jason T; Cross, Eric W; Kedl, Ross M (2017) Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat Rev Immunol 17:391-400
Kedl, Ross M; Seder, Robert (2017) Editorial overview: Vaccines. Curr Opin Immunol 47:A1-A2
White, Jason T; Cross, Eric W; Burchill, Matthew A et al. (2016) Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun 7:11291
Pennock, Nathan D; Kedl, Justin D; Kedl, Ross M (2016) T Cell Vaccinology: Beyond the Reflection of Infectious Responses. Trends Immunol 37:170-180
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471

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