Investigating the role of interleukin-22 in thymus function

描述(申请人提供)：胸腺的内源性再生是一种重要的功能，可以在感染、休克或常见的癌症治疗(如细胞减少性化疗或放射治疗)后恢复免疫能力。胸腺的再生能力随着年龄的增长而减弱，这仍然是一个鲜为人知的领域。这与异基因造血干细胞移植(allo-HSCT)的受者尤其相关，他们在移植后由于细胞还原调节和移植物抗宿主病(GVHD)而经历长期的T细胞缺陷，导致感染和恶性复发的发病率和死亡率增加。因此，这项建议的主要目的是了解内源性胸腺再生的潜在过程，以便将其开发为临床相关的免疫恢复策略。白介素22(IL-22)是新近发现的一种细胞因子，由辅助性T细胞(Th)-17细胞和天然淋巴样细胞(ILCs)分泌，促进肠道、肺和皮肤上皮细胞的天然免疫和动态平衡。我们最近揭示了一个以IL-22为中心的胸腺再生网络，该网络由发育中的胸腺细胞的CD4+CD8+双阳性(DP)耗尽所触发。尽管在基线时，IL-22缺乏对于正常的胸腺生成是多余的，但IL-22缺陷小鼠的胸腺恢复受到损害，而野生型小鼠的胸腺内IL-22水平在胸腺损伤后显著增加。IL-22通过胸腺上皮细胞(TECs)传递信号，促进胸腺上皮细胞的增殖和存活。胸腺损伤后，抗辐射的固有淋巴样细胞(ILCs)以IL-23依赖的方式上调IL-22。重要的是，给予重组IL-22可促进胸腺损伤后的修复。这些发现突出了胸腺再生的内源性网络，其中1)DP胸腺细胞的枯竭触发2)DC上调IL-23，从而诱导3)胸腺ILC产生IL-22。这一系列事件导致支持上皮微环境的再生，并最终使胸腺生成恢复活力。基于这些发现，我们假设(A)IL-22介导的再生将被转化为功能增强的T细胞重建，(B)胸腺中的内源性再生途径是由与DP胸腺细胞的丧失及其通常产生的负面信号固有地联系在一起的损伤感知机制触发的，(C)I-22直接促进TEC的增殖，但也增强其对额外营养因子的反应能力，以及(D)IL-22再生途径的破坏是慢性胸腺退化(包括年龄相关性萎缩)的基础。探索IL-22介导的再生的功能翻译是我博士后工作的自然进展，并将构成本提案的K99指导阶段。这些研究的逻辑延伸，探索IL-22再生途径的潜在机制和影响，将在本提案的独立R00阶段进行探索。这项建议中概述的机制和临床前研究有可能确定胸腺再生的一条重要的新途径，这可能导致临床方法来增强T细胞免疫，不仅适用于allo-HSCT的接受者，也适用于因衰老(淋巴萎缩)、自身免疫性疾病、遗传原因(如SCID)、感染性疾病(HIV、乙肝/C)、皮质类固醇、休克、放化疗和辐射损伤(核事故或恐怖主义)而患有T细胞缺陷的个人。

DESCRIPTION (provided by applicant): Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection, shock or common cancer therapies such as cytoreductive chemo- or radiation therapy. Thymic regenerative capacity diminishes with age and remains a poorly understood area. This is particularly relevant for recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who experience prolonged post-transplant T cell deficiency caused by cytoreductive conditioning and graft-versus- host disease (GVHD), which results in increased morbidity and mortality from infections and malignant relapse. Therefore, the main goal of this proposal is to understand the proceses underlying endogenous thymic regeneration so that they may be exploited into clinically relevant strategies for immune rejuvenation. Interleukin-22 (IL-22) is a recently described cytokine that is produced by T-helper (Th)-17 cells and innate lymphoid cells (ILCs) and promotes innate immunity and homeostasis of epithelial cells in the intestines, lung and skin. We have recently revealed a network of thymic regeneration centred on IL-22 and triggered by the depletion of CD4+CD8+ double positive (DP) developing thymocytes. Although at baseline IL-22 deficiency was redundant for normal thymopoiesis, thymic recovery was impaired in IL-22-deficient mice and intrathymic levels of IL-22 were significantly increased in wildtype mice following thymic injury. IL-22, which signalled through thymic epithelial cells (TECs) and promoted their proliferation and survival, was upregulated by radio- resistant innate lymphoid cells (ILCs) after thymic injury in an IL-23 dependent manner. Importantly, administration of recombinant IL-22 enhanced repair folowing thymic injury. These findings highlight an endogenous network of thymus regeneration whereby 1) the depletion of DP thymocytes triggers 2) upregulation of IL-23 by DCs, which induces 3) the production of IL-22 by thymic ILCs. This cascade of events leads to regeneration of the supporting epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis. Based on these findings, we hypothesize that (a) IL-22-mediated regeneration will be translated into functionally enhanced T cell reconstitution, (b) endogenous regenerative pathways in the thymus are triggered by a damage-sensing mechanism intrinsically tied to the loss of DP thymocytes and a negative signal they typically produce, (c) I-22 directly promotes the proliferation of TECs but also enhances their capacity to respond to additional trophic factors, and (d) breakdown of IL-22 regenerative pathways underlie chronic thymic involution, including age-related atrophy. Exploring the functional translation of IL-22-mediated regeneration is a natural progression of my postdoctoral work and will constitute the K99 mentored phase of this proposal. A logical extension of these studies, exploring the underlying mechanisms and implications of the IL-22 regenerative pathway, will be explored in the independent R00 phase of this proposal. The mechanistic and pre-clinical studies outlined in this proposal have the potential to define an important novel pathway in thymic regeneration, which could result in clinical approaches to enhance T cell immunity, not only for recipients of allo-HSCT, but also for individuals with T cell deficiencies due to aging (lymphoid atrophy), autoimmune diseases, genetic causes (such as SCID), infectious diseases (HIV, hepatitis B/C), corticosteroids, shock, radio- or chemo-therapy and radiation injury (nuclear accident or terrorism).