# Strength of TCR:self-pMHC interactions in the periphery instructs CD4+ T help cell responses

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $470,785

## Abstract

PROJECT SUMMARY
Effective vaccines remain elusive for many deadly diseases; therefore, it is critical that we better understand how
the immune system generates a robust, neutralizing antibody response to vaccination so that we may enhance
this type of response in future vaccine design. B cells are the producers of high-affinity antibodies, however, it is
the CD4+ T cells that provide the cytokines and co-stimulatory molecules necessary to drive this B cell fate and
establish long-term humoral immunity. This is why it is critical that we better understand the development and
function of specific CD4+ T cell subsets involved in generating this type of response. After a primary infection or
vaccination, some activated CD4+ T cells become a specialized subset specifically known to provide direct B cell
help: T follicular helper (Tfh) cells. What commits T cells to the Tfh cell fate is still unknown. Our novel approach
leverages the CD4+ T cell response against the immunodominant LLO epitope from Listeria in B6 mice, using
two defined CD4+ TCR transgenic lines and polyclonal T cells. The two naive T cells differ in their tonic signaling
mediated through the TCR recognition of self-pMHC. Naive CD4+ T cells with low tonic signaling have a high
basal metabolism, respond robustly in a primary in vivo response, and develop into Tfh and TEM cells. Conversely,
naive CD4+ T cells with high tonic signaling have a low basal metabolism, and poorly form Tfh cells. The premise
of this proposal is that the strength of TCR:self-pMHC reactivity (tonic signaling) is deterministic for establishing
the basal metabolism and the subsequent Tfh response. In Aim 1, we will establish whether a direct relationship
exists between tonic signaling and the development of Tfh following antigen exposure. To this end, we will use
our novel knock-in mouse line, Scn5a+. Expression of th Scn5a voltage gated sodium channel allows us to
increase tonic signaling in CD4+ T cells independent of TCR signaling. We will decrease tonic signaling using a
newly developed conditional knockout allele of H-2DM. Tfh helper function will be tested using an NP-LLO model.
In Aim 2 we will examine how T cell metabolism influences Tfh cell responses. We have identified the glycerol
phosphate shuttle as a key player in the increased metabolism of the LLO-118 T cells. We have now generated
a mouse with a conditional knockout allele of mGPD2 which will be a powerful reagent to explore the role of this
metabolic pathway in LLO-118 and polyclonal CD4+ T cell responses. These findings will deepen our
understanding of Tfh development and may reveal therapeutic targets for vaccine design and autoimmunity.

## Key facts

- **NIH application ID:** 10075219
- **Project number:** 5R01AI139540-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sharon Celeste Morley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $470,785
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075219

## Citation

> US National Institutes of Health, RePORTER application 10075219, Strength of TCR:self-pMHC interactions in the periphery instructs CD4+ T help cell responses (5R01AI139540-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10075219. Licensed CC0.

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