IL-2 Family Cytokines and their Receptors-- Biology of the IL-21 system

人们正在研究IL-2和相关的细胞因子系统，以阐明T细胞在正常、肿瘤和免疫缺陷状态下的免疫反应。在抗原激活T细胞后，T细胞免疫反应的大小和持续时间取决于产生的IL-2的数量、受体的表达水平和每个事件的时间进程。IL-2受体含有IL-2Ra、IL-2Rb和GC三条链。1984年伦纳德博士克隆了IL-2Ra，1986年我们发现了IL-2Rb，1993年报道了GC链突变导致人类X-连锁严重联合免疫缺陷(XSCID，具有T-B+NK表型)。我们在1995年报道了GC相关激酶JAK3的突变导致了一种与XSCID难以区分的常染色体隐性形式的SCID，并在1998年报道了T-B+NK+SCID是由IL7R基因突变引起的。根据我们实验室和其他实验室的工作，先前发现GC由IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。 关于IL-21，我们先前克隆了IL-21受体，建立了IL-21转基因小鼠和IL-21R基因敲除小鼠，阐明了IL-21信号转导的机制，发现IL-21促进Th17细胞的分化(介导克罗恩病等病理过程)，并对免疫球蛋白的产生起关键调节作用。我们和其他人认为IL-21在自身免疫性疾病中起关键作用，包括狼疮和1型糖尿病，并指出IL-21作为抗肿瘤药物的可能用途。我们还分析了IL-21在T滤泡辅助细胞和Th17细胞发育中的作用，并在一项合作研究中产生了数据，表明IL-21是晚期同种免疫反应中的抗耐受细胞因子。我们之前还发现，IL-21信号对于CD8 T细胞的生存和记忆细胞的形成是必需的，以应对痘苗病毒感染，并且IL-21在决定小鼠肝炎模型的年龄相关免疫反应中起关键作用，这一发现有助于解释为什么年轻患者IL-21的产生减少可能会阻止关键的CD8 T和B细胞反应，大多数成年人病毒清除，新生儿和儿童慢性乙肝病毒清除。我们先前也发现IL-21促进对肺炎病毒(PVM)的致病应答，而PVM与人类呼吸道合胞病毒高度相关。有趣的是，在IL21r缺陷小鼠感染PVM后，中性粒细胞在肺中的渗透较少，CD8、CD4和γ-Delta T细胞的数量也较少。提示IL-21在PVM的炎症反应中起重要作用，抑制PVM的作用可能是治疗PVM和其他潜在病毒感染的机制之一。最后，通过Tom Tedder，我们之前展示了IL-21可以扩展产生IL-10的B调节细胞(B10细胞)。在本年度，我们继续研究IL-21的生物学作用。 此前，我们证明了IL-21通过依赖于STAT3和IRF4的反应元件来调节编码BLIMP1的Prdm1基因的表达。这导致我们先前发现，与其在B细胞中与PU.1合作通过Ets-IRF复合元件(EICE)发挥作用的能力相反，IRF4与BATF/Jun家族蛋白合作在T细胞和B细胞中通过AP1-IRF复合元件(AICE)发挥作用。我们证明了通过这些AICE对重要基因的关键调控，并证明了IRF4、BATF和Jun家族蛋白的协同结合，在BATF缺陷细胞中IRF4结合显著减少，在IRF4缺陷细胞中BATF结合显著减少。今年，我们继续研究AICE和IRF4/BATF/JUN/STAT3复合体的重要性。 IL-21对T细胞和B细胞有广泛的作用，但对其在先天免疫中的作用知之甚少。以前，我们曾报道IL-21通过STAT3和Bim诱导常规树突状细胞(CDCs)凋亡，而这一作用可被粒细胞-巨噬细胞集落刺激因子(GM-CSF)抑制。我们继续研究IL-21在DC生物学中的作用。 总体而言，我们的研究阐明了GC家族细胞因子IL-21的生物学和作用机制。我们的发现与自身免疫和癌症有关，也与T细胞和B细胞活动的基本控制有关。

IL-2 and related cytokine systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, JAK3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Related to IL-21, we previously cloned the IL-21 receptor, generated IL-21 transgenic mice and IL-21R knockout mice, elucidated the mechanism of IL-21 signaling, showed IL-21 drives differentiation of Th17 cells (which mediate pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. We and others implicated IL-21 as serving a key role in autoimmune disease, including lupus and type 1 diabetes, and indicated the possible utility of IL-21 as an anti-tumor agent. We also analyzed the role of IL-21 related to the development of T follicular helper cells and Th17 cells and generated data in a collaborative study that IL-21 is anti-tolerogenic cytokine in the late-phase alloimmune response. We also previously found that IL-21 signaling is required for CD8 T cell survival and memory cell formation in response to vaccinia viral infection and that IL-21 was pivotal in determining age-dependent immune responses in a mouse model of hepatitis, a finding that helps to explain why decreased production of IL-21 in younger patients may prevent critical CD8 T and B cell responses, with viral clearance in most adults and chronic HBV in neonates and children. We previously also found that IL-21 promotes the pathogenic response to pneumonia virus of mice (PVM), which is highly related to human respiratory syncytial virus. Interestingly, after infection of Il21r-deficient mice with PVM, there was less infiltration of neutrophils and fewer CD8, CD4, and gamma-delta T cell numbers in the lungs. These data indicated that IL-21 plays an important role in mediating the inflammatory response to PVM and suggest that inhibiting the action of PVM could represent a mechanism for treatment PVM and potentially other viral infections. Finally, with Tom Tedder, we previously showed that IL-21 could expand B regulatory cells that produce IL-10 (B10 cells). In the current year, we continued our studies on the biological actions of IL-21. Previously, we demonstrated that IL-21 regulated expression of the Prdm1 gene that encodes BLIMP1 via a response element that depends on STAT3 and IRF4. This led to our prior discovery that in contrast to its ability to cooperate with PU.1 in B cells to act via Ets-IRF composite elements (EICEs), IRF4 cooperates with BATF/JUN family proteins to act via AP1-IRF composite elements (AICEs) in T cells, as well as in B cells. We demonstrated critical regulation of important genes via these AICEs and demonstrated cooperative binding of IRF4, BATF, and JUN family proteins, with markedly diminished IRF4 binding in Batf-deficient cells and markedly diminished BATF binding in Irf4-deficient cells. In the current year, we have continued our studies of AICEs and the importance of the IRF4/BATF/JUN/STAT3 complex. IL-21 has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Previously, we reported that IL-21 induces apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). We have continued our studies of the role of IL-21 in DC biology. Overall, our studies have elucidated the biology and mechanism of action by the gc family cytokine IL-21. Our findings are relevant to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions.