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 CIPN. Neuronal MHCII-dependent activation of CD4+ T cells represents a novel
mechanism for neuro-immune communication that could be utilized for therapeutic intervention.
