Combined immunodeficiencies - understanding the limiting factors in T cell mediated control of viral infections and immune homeostasis.

T细胞免疫对于控制大多数感染很重要。该项目的总体目标是进一步确定人类T细胞免疫的分子基础及其与控制传染病和免疫失调疾病的相关性。我们将采取务实和有针对性的方法来实现这一目标。在实用的方法中，我们将研究通过P-CID研究的表型筛选确定的个体患者，以更好地了解其疾病的分子和免疫学基础。在这些研究中，研究的生物学领域——尽管与T细胞免疫学有关——不能完全先验地定义。将使用两种方法：(i)表征联合免疫缺陷的表型和功能基础（ii）鉴定导致联合免疫缺陷的新型遗传疾病。在靶向方法中，我们将重点关注我们在一组具有异常严重表型的“泄漏”X-SCID患者中观察到的共同γ链中的一个特定突变。进一步表征这种突变的后果将在两方面的实验中进行：（iii） p.a g222cys突变对人类细胞细胞因子信号传导的细胞和分子影响分析（iv） p.a g222cys和其他亚型突变对逆转录小鼠T和NK细胞发育和功能、B细胞功能和抗病毒防御的影响。我们期望这个项目的结果将发现与人类CID相关的T细胞免疫受损的新分子原因，并表征这些突变的免疫学后果。此外，他们将在特定的模型情况下说明，在T细胞免疫部分受损的情况下，影响其他免疫细胞群的缺陷如何影响表型。

T cell immunity is important for the control of most infections. The overall aim of this project is to further define the molecular basis of human T cell immunity and its relevance for the control of infectious diseases as well as for diseases of immune dysregulation. We will use both a pragmatic and a targeted approach to achieve this goal. In the pragmatic approach, we will study individual patients identified through the phenotypic screen of the P-CID study to better understand the molecular and immunological basis of their disease. In these studies, the biological area of investigation - although connected to T cell immunology - cannot be fully defined a priori. Two approaches will be used: (i) Characterization of the phenotypic and functional basis of combined immunodeficiency (ii) Identification of novel genetic disorders causing combined immunodeficiency In the targeted approach, we will focus on one particular mutation in the common gamma chain that we have observed in a cohort of patients with "leaky" X-SCID with an unusually severe phenotype. Further characterization of the consequences of this mutation will be performed in two lines of experimentation: (iii) Analysis of the cellular and molecular consequences of the p.Arg222Cys mutation for cytokine signaling in human cells (iv) Impact of the p.Arg222Cys and other hypomorphic mutations on T and NK cell development and function, B cell function and antiviral defense in retrogenic mice We expect that the results from this project will identify novel molecular causes for impaired T cell immunity associated with human CID and characterize the immunological consequences of such mutations. Moreover, they will illustrate in a particular model situation, how defects affecting other immune cell population influence the phenotype in situations of partially impaired T cell immunity.