Project 1: Functional consequences of STAT3 GOF on immune cell signaling

Project Summary/Abstract Primary immune dysregulation syndromes are group of rare monogenic disorders affecting immune tolerance and leading to early-onset immunodeficiency, autoimmunity, and risk of malignancy. STAT3 gain-of-function (GOF) syndrome was recently described as a primary immune dysregulation syndrome causing early-onset

polyautoimmunity and lymphoproliferation. While we have a good understanding of the genetic basis of STAT3 GOF syndrome, the underlying mechanisms of immune dysregulation and relevant cell types that should be targeted for therapy of disease are less clear. We hypothesize that dysregulation of T cells in STAT3 GOF leads

to disease and that this is a relevant cell type that can be targeted for therapy. We will investigate this hypothesis in collaboration with Drs. Anderson and Marson by deeply interrogating the immune response in patients with STAT3 GOF and using new mouse models of disease. The long-term goals of this project are to understand how

immune tolerance is lost with STAT3 GOF to gain a better understanding of mechanisms of immune tolerance in humans and provide personalized and precision therapy for the treatment of this and other rare immunologic diseases of childhood. In this project we will investigate mechanisms of immune dysregulation by: 1) identifying

the variants in STAT3 that alter function and interrogating immune cells signals that are altered by STAT3 GOF using primary patient samples and cells from murine models of STAT3 GOF using sequencing techniques; 2) Identifying novel autoantibodies from patient samples using a broad-based approach; and 3) Investigating a

model of skin inflammation in STAT3 GOF mice to determine relevant cell types in a disease model and interrogate the response to JAK inhibition.