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

IL-2和相关的细胞因子系统正在研究中，以澄清正常，肿瘤和免疫缺陷状态下的T细胞免疫应答。在T细胞被抗原激活后，T细胞免疫应答的幅度和持续时间由产生的IL-2的量、表达的受体水平和每个事件的时间过程决定。IL-2受体含有三条链，IL-2 Ra、IL-2 Rb和gc。伦纳德博士于1984年克隆了IL-2 Ra，我们于1986年发现了IL-2 Rb，并于1993年报道了人类中GC链突变导致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JAK 3的突变导致与XSCID难以区分的常染色体隐性形式的SCID，并且在1998年报道了T-B+NK+ SCID由IL 7 R基因突变引起。基于我们实验室和其他实验室的工作，先前显示gc被IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。 与IL-21相关，我们先前克隆了IL-21受体，产生了IL-21转基因小鼠和IL-21 R敲除小鼠，阐明了IL-21信号传导的机制，表明IL-21驱动Th 17细胞的分化（介导克罗恩病等病理过程），并严格调节免疫球蛋白的产生。我们和其他人认为IL-21在自身免疫性疾病（包括狼疮和1型糖尿病）中起关键作用，并指出IL-21可能用作抗肿瘤药物。我们还分析了IL-21与T滤泡辅助细胞和Th 17细胞发育相关的作用，并在一项合作研究中获得了IL-21是晚期同种免疫应答中的抗耐受性细胞因子的数据。我们以前还发现，IL-21信号传导是响应于牛痘病毒感染的CD 8 T细胞存活和记忆细胞形成所必需的，并且IL-21在确定肝炎小鼠模型中的年龄依赖性免疫应答中是关键的，这一发现有助于解释为什么年轻患者中IL-21的产生减少可能会阻止关键的CD 8 T和B细胞应答，在大多数成人中病毒清除，在新生儿和儿童中慢性HBV。我们以前也发现IL-21促进小鼠肺炎病毒（PVM）的致病反应，这是高度相关的人呼吸道合胞病毒。有趣的是，在用PVM感染IL 21 r缺陷小鼠后，肺中中性粒细胞浸润较少，CD 8，CD 4和γ-δ T细胞数量较少。这些数据表明，IL-21在介导对PVM的炎症反应中起重要作用，并表明抑制PVM的作用可能代表治疗PVM和潜在的其他病毒感染的机制。最后，与Tom Tedder一起，我们先前表明IL-21可以扩增产生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。 以前，我们证明了IL-21通过依赖于STAT 3和IRF 4的反应元件调节编码BLIMP 1的Prdm 1基因的表达。这导致我们先前的发现，与其在B细胞中与PU. 1合作以通过Ets-IRF复合元件（EICE）起作用的能力相反，IRF 4与BATF/JUN家族蛋白合作以通过T细胞以及B细胞中的AP 1-IRF复合元件（AICE）起作用。我们证明了通过这些AICE对重要基因的关键调控，并证明了IRF 4，BATF和JUN家族蛋白的协同结合，在Batf缺陷细胞中IRF 4结合显著减少，在Irf 4缺陷细胞中BATF结合显著减少。在本年度，我们继续研究AICE和IRF 4/BATF/JUN/STAT 3复合物的重要性。 IL-21对T细胞和B细胞具有广泛的作用，但其在先天免疫中的作用知之甚少。以前，我们报道了IL-21通过STAT 3和Bim诱导常规树突状细胞（cDCs）凋亡，并且这被粒细胞-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。 总之，我们的研究已经阐明了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.