Regulation of pathogen-specific T-cell responses in patients with Hyper-IgE syndrome (HIES)

Hyper-IgE syndrome (HIES) is a rare genetic disease cause by a defect of “Signal transducer and activation of transcription (STAT) 3”, which plays a key role in regulating immune responses against pathogens. HIES patients have indeed on the one hand an inefficient response against opportunistic pathogens and suffer consequently from recurrent infections. This immunological defect is caused by an insufficient production of two soluble mediators, called Interleukin(IL)-17 and IL-22, by a central class of immune cells, the CD4+ T lymphocytes. On the other hand, as also indicated by the name of the disease, HIES patients have an exaggerated antibody production of the Immunoglobulin E (IgE) class, which induce allergic reactions like eczema. This second immunological defect is also the consequence of an inappropriate function of CD4+ T lymphocytes, because the latter can also produce soluble mediators, called IL-4 and IL-21, that induce the production of IgE. In this project, we will study the precise cellular and molecular mechanisms that leads to uncontrolled IgE production in the absence of STAT3 in CD4+ T lymphocytes from HIES patients and STAT3-deficient mice to understand if blocking IL-4 or IL-21 with specific antibodies could reduce IgE production and consequently probably also eczema in HIES patients. Moreover, we will try to expand and educate CD4+ T lymphocytes from HIES patients and STAT3-deficient mice that recognize the relevant opportunistic pathogens to produce IL-22 and/or IL-17 in a stable manner. These modified cells could then be reinfused into the same patients to improve the control of opportunistic infections. In addition to these putative future clinical impacts, this project will significantly advance our understanding of the role of STAT3 in CD4+ T lymphocytes and the immune system.