# Detection and Activation of CD4+ T cells with Low Affinity TCRs

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $383,226

## Abstract

Project Summary/Abstract
CD4+ helper T (Th) cells are responsible for host immunity to phagosomal pathogens and augment antibody
and cytotoxic T cell-mediated responses. They also cause autoimmunity and can participate in immune
responses to tumors. Th cells carry out these functions by using antigen receptors (TCRs) to recognize
epitopes consisting of peptides (p) bound to major histocompatibility complex class II molecules (MHCII)
displayed on various host cells. Fluorochrome-labeled p:MHCII tetramers and flow cytometry have been critical
tools for studying immune responses by epitope-specific polyclonal Th cells. It has become clear, however,
that p:MHCII tetramers do not detect TCRs at the low end of the relevant affinity spectrum. This limitation has
created a knowledge gap about the roles that Th cells with low-affinity TCRs play in immune responses to
infections and cancer. We hypothesized that p:MHCII tetramers underperform because their stalk regions do
not bind to CD4 molecules on Th cells. We used molecular evolution to select an MHCII molecule with
improved CD4 binding (MHCII-4E) and found that p:MHCII-4E tetramers are superior to conventional reagents
at detecting Th cells with low affinity TCRs. We will use these innovative reagents to identify the roles that Th
cells with low affinity TCRs play in immune responses to persistent and chronic infections, and an autoimmune
disease of the central nervous system. We will also test a p:MHCII-4E-based vaccine in a B cell leukemia
model. Completion of these aims will fill basic knowledge gaps about the composition of Th repertoires for self
and foreign epitopes and provide proof of principle for new therapies targeted to low affinity Th cells.

## Key facts

- **NIH application ID:** 10112167
- **Project number:** 5R01AI143826-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Marc Kevin Jenkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,226
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112167

## Citation

> US National Institutes of Health, RePORTER application 10112167, Detection and Activation of CD4+ T cells with Low Affinity TCRs (5R01AI143826-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10112167. Licensed CC0.

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