2026/02/25 by Giorgia Moschetti, Chiara Vasco, Francesca Clemente +16 · 1 voice
Immunology and Microbiology · #Immunodeficiency and Autoimmune Disorders #Psoriasis: Treatment and Pathogenesis #T-cell and B-cell Immunology
paper · doi:10.1111/all.70266
openalex publication_date 2026/02/25 · openalex created_date 2026/02/26 · openalex updated_date 2026/05/21
ABSTRACT Background Autosomal Dominant‐Hyper‐IgE Syndrome (AD‐HIES) is caused by dominant‐negative (DN) STAT3 mutations and characterized by high IgE levels, a lack of Th17‐cells, and recurrent infections with extracellular pathogens. We previously identified an enigmatic population of IL‐10 producing CCR6 + B‐helper T‐cells and investigated here their relationship to Th17‐cells and STAT3 signaling requirements. Methods Human blood lymphocytes were analyzed by multiparametric flow cytometry in healthy donors and AD‐HIES patients. Analysis was performed by conventional gating or with bioinformatic tools. FACS‐purified T‐cell subsets were activated in vitro and Th17 differentiation assessed. T‐cell antigen specificities were assessed by activation with heat‐killed pathogens or antigenic peptide pools. B helper capacities were determined according to antibody secretion in B‐T co‐cultures by ELISA. Results CCR6 + Th‐cells that lacked subset‐defining differentiation markers (“CCR6 SP ”) were mostly non‐polarized central memory T‐cells (T CM ) that produced IL‐10 and expressed RORγt. They were pre‐committed to a Th17 fate, since TCR stimulation in the absence of polarizing cytokines induced efficient Th17 differentiation. The latter was promoted by an autocrine loop of STAT3‐activating cytokines. CCR6 + Th‐cells were reduced in patients with DN‐STAT3 mutations but contained activated CCR6 SP T‐cells that produced IL‐10 and responded vigorously to AD‐HIES‐associated pathogens. These residual CCR6 + Th‐cells provided B‐cell help for IgG and IgE production. Conclusions Th17 differentiation in AD‐HIES patients was not completely impaired but arrested at an intermediate stage of IL‐10‐producing “pre‐Th17”‐cells. Surprisingly, DN‐STAT3 mutations did not inhibit IL‐10 production by CD4 + T‐cells. Pre‐Th17‐cells were activated by AD‐HIES‐associated pathogens and possessed B‐helper functions, suggesting that they are not protective but may promote aberrant IgE production.