Sex-dependent control of nociception by meningeal regulatory T cells

PROJECT SUMMARY Women are up to three times more likely to experience chronic pain compared to men. Both immune cells and neurons along the pain pathway express receptors for sex hormones, indicating multiple potential sites for modulation. Additionally, men and women exhibit different immune robustness, and T cells appear to be involved in sexually dimorphic pain signaling. Despite evidence of strong interaction between sex hormones, the immune system, and pain, the precise mechanisms underlying these differences are unknown. Regulatory T cells (Tregs), a subset of T cells, play a crucial role in maintaining immunotolerance and tissue homeostasis. Our recent findings show that Tregs in the spinal cord meninges release endogenous opioids acting on the delta opioid receptor in primary afferent neurons. This neuroimmune circuit modulates pain hypersensitivity in female mice in a hormone-dependent manner and underlies pregnancy-induced analgesia. Paralleling human data, we observed increased pain sensitivity in female, but not male, offspring of mothers with chronic pain, in a T cell-mediated, maternally derived manner. The proposed research will use behavioral pain assessment, hormone replacement, mouse genetics, and transcriptomics to elucidate how sex hormones and pregnancy modulate this pathway to confer antinociceptive action specifically in females and how this pathway may influence pain sensitivity in the female progeny. During the K99 phase, I will investigate which sex hormones restrict this opioid circuit to females and identify their site of action within the pathway in nulliparous mice. I will also explore how gestation modulates this neuroimmune opioid circuit to induce pregnancy-induced analgesia. In the R00 phase, I will examine how chronic pain during pregnancy increases pain sensitivity in female offspring. This will involve studying potential alterations in maternal care, immune responses, or T cell-secreted factors and how they impact the neuronal transcriptome of the progeny to induce increased pain sensitivity. To support my scientific and career development towards independence, I have assembled a Scientific Advisory Committee comprising leading experts in sex differences, immunology, gestation, and transcriptomics at UCSF. Along with my mentor, they will oversee my progress and successful path towards an independent researcher in the field of neuroimmunology of pain.