Germline STAT3 gain-of-function mutations in primary immunodeficiency: Impact on the cellular and clinical phenotype

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor involved in regulation of immune cell activation and differentiation. Recent discoveries highlight the role of germline activating STAT3 mutations in inborn errors of immunity characterized by early-onset multi-organ autoimmunity and lymphoproliferation. Much progress has been made in defining the clinical spectrum of STAT3 GOF disease and unraveling the molecular and cellular mechanisms underlying this disease. In this review, we summarize our current understanding of the disease and discuss the clinical phenotype, diagnostic approach, cellular and molecular effects of STAT3 GOF mutations and therapeutic concepts for these patients.

Keywords: Autoimmunity; Inborn errors of immunity; Lymphoproliferation; STAT3 GOF; T cell.

Fig. 1

Frequency of clinical symptoms observed in STAT3 GOF, APDS, CTLA4 and NFkB 1 associated diseases. Data from Ref. [14] were complemented with new patient reports from Refs. [15,16,[21], [22], [23], [24], [25], [26], [27]]. Patients appearing in more than one report were removed to the best of our ability resulting in a total of 83 STAT3 GOF patients. Reference values for APDS (n = 77), CTLA4 (n = 133) and NFkB1 (n = 157.) were taken from Refs. [[28], [29], [30]]. n.r.: not reported.

Fig. 2

Overview of the STAT3 signaling pathway. A cytokine (here IL-6) binds to its cognate receptor, which leads to phosphorylation of Janus Kinases (JAKs). Activated JAKs phosphorylate STAT3, which allows it to form dimers, shuttle to the nucleus and act as a transcription factor. The three main negative regulators of STAT3 activity are shown in red. SOCS3 inhibits the catalytic activity of JAKs preventing STAT3 phosphorylation, PTPs (phosphotyrosine phosphatases) dephosphorylate STAT3 dimers and PIAS3 prevents DNA binding of STAT3 dimers. In STAT3 GOF disease, the signaling cascade can be influenced at different levels leading to a variable combination of (1) increased phosphorylation or decreased dephosphorylation, (2) altered dimer formation (including heterodimers), (3) changes in nuclear translocation of the dimer, (4) altered DNA binding kinetics and motives and (5) changes in the target gene expression. The effect on non-canonical functions (6) and heterodimerization of different STAT molecules remains to be fully characterized.

Fig. 3

Schematic of the STAT3 protein showing the location of all reported (02/2021) germline STAT3 GOF mutations within the STAT3 domains. All mutations were reported in at least one patient with clinical symptoms consistent with STAT3 GOF disease. For mutations depicted in black, GOF activity was confirmed by either in vitro testing using the luciferase assay or by increased pSTAT3 in ex vivo testing. For mutations depicted in green, no validation of GOF activity was reported. Detailed information can be found in Supplemental Table 1.