# Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy

> **NIH NIH R01** · UNIVERSITY OF NEW ENGLAND · 2022 · $342,189

## Abstract

Project Summary/Abstract
Chemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painful
neuropathy, posing a major challenge to the successful treatment of cancer. Recent reports demonstrate that
male mice lacking T cells have prolonged mechanical hypersensitivity after treatment with paclitaxel (PTX),
and only the intravenous transfer of CD8+, but not CD4+, T cells reduced the hypersensitivity. Our preliminary
in vivo data demonstrates female mice have 2-fold more CD4+ T cells in the DRG than male and
ovariectomized (OVX) female mice, and neuronal injury induced by PTX robustly increases anti-inflammatory
CD4+ T cells in the DRG only in estrogen-competent female mice. CD4+ T cell depletion in female mice prior to
PTX results in an increase in mechanical hypersensitivity 3 days post-PTX. Our results suggest a previously
unexplored hormone and sex difference in CD4+ T cells and the severity of chemotherapy-induced peripheral
neuropathy (CIPN). PTX is primarily used to treat ovarian, breast, and non-small cell lung cancer with post-
menopausal patients at an increased risk of CIPN; therefore, preventative measures would be invaluable for
women. The mechanism by which CD4+ T cells reduce the severity of PIPN is unknown. In our preliminary
studies, DRG neurons from female mice have the capacity to activate CD4+ T cells to secrete anti-
inflammatory cytokines. Published RNA-seq datasets of DRG neurons show that DRG neurons express
MHCII, a protein directly involved in T cell activation. Our central hypothesis is that PTX administration in
female mice increases MHCII on sensory neurons to stimulate the paracrine release of anti-inflammatory
cytokines by resident CD4+ T cells to suppress CIPN. In Aim 1, we will determine the extent to which estrogen-
driven CD4+ T cells reduce the severity of PTX-induced peripheral neuropathy. Estrogen is known to induce
proliferation of blood CD4+ T cells, but it is unknown if this occurs in the DRG. We predict that estrogen
signaling in CD4+ T cells will increase the number of resident CD4+ T cells in the DRG to secrete anti-
inflammatory cytokines in response to PTX. We expect CD4+ T cells to ameliorate CIPN in female, but not
male mice. In Aim 2, we will quantify the extent PTX can enhance MHCII on DRG neurons to induce anti-
inflammatory CD4+ T cell cytokine production. We predict PTX-induced inflammation will increase neuronal
MHCII to elicit an anti-inflammatory CD4+ T cell response in the DRG of female, but not male mice. In Aim 3,
we will determine the degree in vivo activation of neuroprotective CD4+ T cells can reduce and reverse PTX-
induced peripheral neuropathy. We predict that activated CD4+ T cells will dampen and reverse CIPN in
female, but not male mice, unless pre-treated with estrogen. Completion of these aims will provide compelling
evidence that CD4+ T cells in the DRG of females are neuroprotective and anti-nociceptive, and can be
exploited to prevent or resolve...

## Key facts

- **NIH application ID:** 10522294
- **Project number:** 1R01CA267554-01A1
- **Recipient organization:** UNIVERSITY OF NEW ENGLAND
- **Principal Investigator:** Diana J Goode
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $342,189
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522294

## Citation

> US National Institutes of Health, RePORTER application 10522294, Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy (1R01CA267554-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10522294. Licensed CC0.

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