Novel expression of MHC class II on DRG neurons can directly activate CD4+ T cells contributing to the resolution of neuropathic pain

DRG 神经元上 MHC II 类的新表达可直接激活 CD4 T 细胞，有助于缓解神经性疼痛

• 批准号: 10551575
• 负责人: Diana J Goode
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551575
• 关键词: Novel; expression; MHC; class; II

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 antinflammatory 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.

由于出现衰弱和疼痛的神经病变，化疗药物通常是剂量限制性的，这对癌症的成功治疗构成了重大挑战。最近的报道表明，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，并且仅静脉内转移CD 8 + T细胞而不是CD 4 + T细胞降低了超敏性。我们的初步体内数据表明，雌性小鼠DRG中的CD 4 + T细胞是雄性和卵巢切除（OVX）雌性小鼠的2倍，PTX诱导的神经元损伤仅在雌激素活性雌性小鼠中显著增加DRG中的抗炎CD 4 + T细胞。PTX前雌性小鼠中的CD 4 + T细胞耗竭导致PTX后3天机械超敏反应增加。我们的研究结果表明，以前未探索的激素和性别差异的CD 4 + T细胞和化疗诱导的周围神经病变（CIPN）的严重程度。PTX主要用于治疗卵巢癌、乳腺癌和非小细胞肺癌，绝经后患者CIPN风险增加;因此，预防措施对女性非常重要。CD 4 + T细胞降低PIPN严重程度的机制尚不清楚。在我们的初步研究中，来自雌性小鼠的DRG神经元具有激活CD 4 + T细胞以分泌抗炎细胞因子的能力。已发表的DRG神经元的RNA-seq数据集显示，DRG神经元表达MHCII，一种直接参与T细胞活化的蛋白质。我们的中心假设是，雌性小鼠中的PTX给药增加感觉神经元上的MHCII，以刺激驻留的CD 4 + T细胞旁分泌释放抗炎细胞因子，从而抑制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严重程度的程度。已知雌激素可诱导血液CD 4 + T细胞增殖，但尚不清楚这是否发生在DRG中。我们预测，在CD 4 + T细胞中的雌激素信号传导将增加DRG中驻留的CD 4 + T细胞的数量，以响应PTX而分泌抗炎细胞因子。我们预期CD 4 + T细胞可以改善雌性小鼠的CIPN，但对雄性小鼠没有影响。在目的2中，我们将量化PTX可以增强DRG神经元上的MHCII以诱导抗炎性CD 4 + T细胞细胞因子产生的程度。我们预测PTX诱导的炎症将增加神经元MHCII，从而在雌性小鼠而不是雄性小鼠的DRG中引起抗炎性CD 4 + T细胞应答。在目的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诱导的周围神经病变的程度。我们预测，活化的CD 4 + T细胞将抑制和逆转雌性小鼠的CIPN，而不是雄性小鼠，除非预先用雌激素治疗。这些目标的完成将提供令人信服的证据表明，女性DRG中的CD 4 + T细胞具有神经保护作用和抗伤害感受作用，并且可以用于预防或解决CIPN。CD 4 + T细胞的神经元MHCII依赖性活化代表了神经免疫通讯的新机制，可用于治疗干预。