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

项目总结/摘要 化疗药物通常是剂量限制性的，因为出现了使人衰弱和疼痛的症状。 神经病变，对癌症的成功治疗构成重大挑战。最近的报告表明， 缺乏T细胞的雄性小鼠在用紫杉醇（PTX）治疗后具有延长的机械超敏性， 仅静脉输注CD 8 + T细胞而非CD 4 + T细胞可减轻超敏反应。我们的初步 体内数据表明，雌性小鼠DRG中的CD 4 + T细胞是雄性小鼠的2倍， 卵巢切除（OVX）雌性小鼠，PTX诱导的神经元损伤强烈增加抗炎作用。 仅雌激素感受态雌性小鼠DRG中的CD 4 + T细胞。给药前雌性小鼠中的CD 4 + T细胞耗竭 PTX导致PTX后3天机械超敏反应增加。我们的研究结果表明， 未探索的激素和性别差异的CD 4 + T细胞和化疗诱导的外周血淋巴细胞的严重程度 神经病变（CIPN）。PTX主要用于治疗卵巢癌、乳腺癌和非小细胞肺癌， 绝经期患者CIPN的风险增加;因此，预防措施将是无价的， 妇女CD 4 + T细胞降低PIPN严重程度的机制尚不清楚。在我们的初步调查中 研究表明，来自雌性小鼠的DRG神经元具有激活CD 4 + T细胞分泌抗- 炎性细胞因子已发表的DRG神经元的RNA-seq数据集显示，DRG神经元表达 MHCII是一种直接参与T细胞活化的蛋白质。我们的中心假设是， 雌性小鼠增加感觉神经元上的MHCII，以刺激抗炎药的旁分泌释放 细胞因子通过驻留的CD 4 + T细胞来抑制CIPN。在目标1中，我们将确定雌激素- 驱动的CD 4 + T细胞降低PTX诱导的周围神经病变的严重性。雌激素会导致 血液CD 4 + T细胞的增殖，但尚不清楚这是否发生在DRG中。我们预测雌激素 CD 4 + T细胞中的信号传导将增加DRG中驻留的CD 4 + T细胞的数量，以分泌抗CD 4 + T细胞。 炎症细胞因子对PTX的反应。我们预期CD 4 + T细胞可以改善女性CIPN，但不能 雄性老鼠在目标2中，我们将量化PTX可以增强DRG神经元上的MHCII以诱导抗-MHCII的程度。 炎性CD 4 + T细胞细胞因子产生。我们预测PTX诱导的炎症会增加神经元 MHCII在雌性而非雄性小鼠的DRG中引发抗炎性CD 4 + T细胞应答。在目标3中， 我们将确定神经保护性CD 4 + T细胞的体内活化可以减少和逆转PTX的程度。 诱发周围神经病变。我们预测，活化的CD 4 + T细胞将抑制和逆转CIPN。 雌性，但不是雄性小鼠，除非用雌激素预处理。这些目标的实现将提供令人信服的 有证据表明，女性DRG中的CD 4 + T细胞具有神经保护作用和抗伤害性， 用于预防或解决CIPN。CD 4 + T细胞的神经元MHCII依赖性活化代表了一种新的 神经免疫通讯的机制，可用于治疗干预。

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.