Abstract
Background
Heterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an inborn error of immunity characterized by immune dysregulation, recurrent infections and various autoimmune manifestations. However, the precise pathogenic mechanism by which STAT1 GOF contributes to autoimmunity remains elusive.Objective
We sought to determine whether and how STAT1 GOF affects follicular helper T (Tfh) cell differentiation and autoimmune pathogenesis.Methods
Using Stat1 GOF (T385M) mice, we analyzed the effects of STAT1 GOF on the Tfh differentiation and germinal center (GC) responses upon various immune challenging. CUT&Tag and transcriptomic analyses were integrated to dissect how STAT1 GOF contributes to autoimmunity. Further, JAK inhibition and IFN-γ blockade were evaluated in vivo.Results
STAT1-GOF patients showed a bias in cTfh cells toward a CXCR3+ Tfh1-like phenotype. In Stat1 GOF mice, excessive STAT1 activation promoted Tfh differentiation, enhanced GC formation, and disturbed T cell-dependent humoral responses, with immunoglobulin class switching skewed toward IgG2. STAT1 GOF directly targeted Tfh- and Th1-associated genes and drove the development of IFN-γ-producing Tfh1 cells, which was accompanied by autoantibody production and autoimmune manifestations. IFN-γ neutralization reduced autoimmune cellular responses and autoantibody levels in mutant mice.Conclusions
STAT1 GOF promotes aberrant Tfh1 differentiation to drive autoimmunity and dysregulated humoral responses. These findings imply that proper regulation of STAT1 activity within a reasonable magnitude is crucial for ensuring optimal host-protective humoral immunity, and that IFN-γ neutralization may be a promising treatment option for patients with STAT1 GOF and other related autoimmune diseases.