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

• Applicants: Professor Dr. Stephan Ehl; Dr. Klaus Schwarz
• Subject Area: Immunology ; Pediatric and Adolescent Medicine
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260998172

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.

• DFG Programme: Research Grants