Hyperactive STAT1 promotes T_fh1-cell differentiation to trigger autoimmunity

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.

We sought to determine whether and how STAT1 GOF affects T_fh-cell differentiation and autoimmune pathogenesis.

Using Stat1-GOF (T385M) mice, we analyzed the effects of STAT1 GOF on the T_fh differentiation and germinal center responses on various immune challenging. CUT&Tag and transcriptomic analyses were integrated to dissect how STAT1 GOF contributes to autoimmunity. Furthermore, Janus kinase inhibition and IFN-γ blockade were evaluated in vivo.

Patients with STAT1 GOF showed a bias in cT_fh cells toward a CXCR3⁺ T_fh1-like phenotype. In Stat1-GOF mice, excessive STAT1 activation promoted T_fh differentiation, enhanced germinal center formation, and disturbed T-cell-dependent humoral responses, with immunoglobulin class switching skewed toward IgG2. STAT1 GOF directly targeted T_fh- and T_H1-associated genes and drove the development of IFN-γ-producing T_fh1 cells, which was accompanied by autoantibody production and autoimmune manifestations. IFN-γ neutralization reduced autoimmune cellular responses and autoantibody levels in mutant mice.

STAT1 GOF promotes aberrant T_fh1 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.