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

项目摘要/摘要 化疗药物的剂量往往是有限的，因为出现了虚弱和疼痛 神经病变，对癌症的成功治疗构成了重大挑战。最近的报告表明， 缺乏T细胞的雄性小鼠在接受紫杉醇(PTX)治疗后，机械超敏反应时间延长。 仅静脉输注CD8+T细胞，而不输注CD4+T细胞可降低超敏反应。我们的预赛 体内数据显示，雌性小鼠DRG中的CD4+T细胞是雄性小鼠的两倍 去卵巢(OVX)雌性小鼠，PTX诱导的神经元损伤可增强抗炎作用 DRG中的CD4+T细胞仅在雌激素能力强的雌性小鼠中存在。雌性小鼠在感染前的CD4+T细胞耗竭 PTX治疗后3天，机械过敏反应增加。我们的研究结果表明， CD4+T细胞中未知激素和性别差异与化疗后外周血的严重程度 神经病(CIPN)。PTX主要用于治疗卵巢癌、乳腺癌和非小细胞肺癌。 更年期患者患CIPN的风险增加；因此，预防措施对 女人。CD4+T细胞减轻PIPN严重程度的机制尚不清楚。在我们的预赛中 研究表明，雌性小鼠的背根节神经元具有激活CD4+T细胞分泌抗病毒的能力 炎性细胞因子。已发表的背根节神经元的rna-seq数据集显示，背根神经节神经元表达 MHCII，一种直接参与T细胞激活的蛋白质。我们的中心假设是PTX在 雌性小鼠增加MHCII对感觉神经元的刺激旁分泌抗炎释放 常驻的CD4+T细胞抑制CIPN的细胞因子。在目标1中，我们将确定雌激素- 驱动的CD4+T细胞可降低PTX诱导的周围神经病变的严重程度。众所周知，雌激素可以诱导 血液中CD4+T细胞的增殖，但尚不清楚这种情况是否发生在DRG中。我们预测雌激素 CD4+T细胞中的信号将增加驻留在DRG中的CD4+T细胞的数量，以分泌抗 PTX反应中的炎性细胞因子。我们期待CD4+T细胞改善女性CIPN，但不是 雄鼠。在目标2中，我们将量化PTX可以在多大程度上增强DRG神经元上的MHCII以诱导抗 炎症性CD4+T细胞细胞因子的产生。我们预测PTX诱导的炎症将增加神经元 MHCII在雌性小鼠的DRG中诱导抗炎的CD4+T细胞反应，而不是雄性小鼠。在《目标3》中， 我们将确定神经保护性CD4+T细胞在体内的激活程度可以减少和逆转PTX- 诱发周围神经病变。我们预测活化的CD4+T细胞将抑制和逆转CIPN 雌鼠，但不是雄鼠，除非预先用雌激素处理。完成这些目标将提供令人信服的 有证据表明，女性DRG中的CD4+T细胞具有神经保护和抗伤害性，并可以 被利用来防止或解决CIPN。神经元MHCII依赖的CD4+T细胞活化代表了一种新的 可用于治疗干预的神经免疫通讯机制。

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.