Autosomal Dominant Hyper-IgE Syndrome Patients Retain IL10-Producing preTh17-Cells That Are Activated by...

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.

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.

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^SPT-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.

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.