Investigating the role of interleukin-22 in thymus function

描述（由申请人提供）：胸腺内源性再生是一项关键功能，允许在感染，休克或常见癌症治疗（如细胞减少化疗或放射治疗）后更新免疫能力。胸腺再生能力随着年龄的增长而减弱，这仍然是一个知之甚少的领域。这对于同种异体造血干细胞移植（allogeneic hematopoietic stem cell transplantation, alloo - hsct）的受者来说尤其重要，他们在移植后经历由细胞减少条件和移植物抗宿主病（graft- anti - host disease， GVHD）引起的长期T细胞缺乏，导致感染和恶性复发的发病率和死亡率增加。因此，本研究的主要目标是了解内源性胸腺再生的过程，以便将其应用于临床相关的免疫再生策略。白细胞介素-22 （IL-22）是最近发现的一种细胞因子，由辅助性t细胞(Th)-17细胞和先天淋巴样细胞（ILCs）产生，促进肠道、肺和皮肤上皮细胞的先天免疫和稳态。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CD4+CD8+双阳性（DP）胸腺细胞的耗竭触发。尽管在基线时，IL-22缺乏对正常的胸腺生成是多余的，但IL-22缺乏小鼠的胸腺恢复受到损害，野生型小鼠胸腺损伤后胸腺内IL-22水平显著升高。IL-22通过胸腺上皮细胞（TECs）发出信号并促进其增殖和存活，在胸腺损伤后，IL-22以IL-23依赖的方式被放射抗性先天淋巴细胞（ILCs）上调。重要的是，重组IL-22的使用增强了胸腺损伤后的修复。这些发现强调了胸腺再生的内源性网络，其中1)DP胸腺细胞的消耗触发2)dc对IL-23的上调，进而诱导3)胸腺IL-22的产生。这一连串的事件导致支持上皮微环境的再生，并最终导致胸腺再生的恢复。基于这些发现，我们假设(a) il -22介导的再生将转化为功能增强的T细胞重构，(b)胸腺内源性再生途径是由与DP胸腺细胞损失及其通常产生的负信号内在关联的损伤感知机制触发的，(c) I-22直接促进tec的增殖，但也增强了它们对其他营养因子的反应能力。(d) IL-22再生途径的破坏是慢性胸腺退化的基础，包括与年龄相关的萎缩。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，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含义，将在本提案的独立R00阶段进行探讨。本提案中概述的机制和临床前研究有可能定义胸腺再生的重要新途径，这可能导致临床方法来增强T细胞免疫，不仅适用于同种异体造血干细胞移植受体，也适用于由于衰老（淋巴细胞萎缩），自身免疫性疾病，遗传原因（如SCID），感染性疾病（HIV，乙型/丙型肝炎），皮质类固醇，休克，放射或化学治疗和辐射损伤（核事故或恐怖主义）。

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).