| Abstrakt: |
Chemotherapy can be a life-saving treatment, but development of chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity. Recent studies demonstrate that paclitaxel (PTX) increases anti-inflammatory CD4+T cells in the dorsal root ganglia (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. We found that DRG neurons express major histocompatibility II (MHCII) protein, and that reducing neuronal MHCII exacerbates PTX-induced cold hypersensitivity in male and female mice. Furthermore, we demonstrate that CD4+T cells can breach the satellite glial cell barrier and be in close proximity to DRG neurons. Together, these findings suggest the possibility that the T cell receptor (TCR) on CD4+T cells can bind neuronal MHCII. This interaction would resemble the canonical immunological synapse (IS), which precedes CD4+T cell signaling and activation. However, the extent neurons induce CD4+T cell cytokine production to suppress CIPN remains unknown. We hypothesize that IS formation with DRG neurons and subsequent CD4+T cell signaling leads to anti-inflammatory cytokine production, which ultimately suppresses PTX-induced cold hypersensitivity. Using immunocytochemistry and flow cytometry, we show in vitro that DRG neurons formed an IS with CD4+T cells and induced CD4+T cell cytokine production. Moreover, we demonstrate that co-culturing CD4+T cells with DRG neurons from PTX-treated female mice resulted in greater anti-inflammatory IL-4 production than co-culturing with DRG neurons from naïve mice. Collectively, these findings suggest a mechanism by which formation of a TCR-neuronal MHCII complex induces CD4+T cell anti-inflammatory cytokine production to suppress CIPN. Funding: National Institutes of Health grant R01CA267554 (DG). |
