# Transcriptional regulation of vaccine-elicited and infection-elicited CD8+ T cell responses

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

Project Summary
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 naïve 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.

## Key facts

- **NIH application ID:** 9840859
- **Project number:** 5R01AI066121-13
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Ross M Kedl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2007-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840859

## Citation

> US National Institutes of Health, RePORTER application 9840859, Transcriptional regulation of vaccine-elicited and infection-elicited CD8+ T cell responses (5R01AI066121-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9840859. Licensed CC0.

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