AD-HIES patients retain preTh17-cells that produce IL10 with opportunistic pathogens and induce IgE
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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 signalling requirements.
Methods
Human blood lymphocytes were analysed 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 were mostly non-polarised 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 polarising 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 + T CM 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 promote aberrant IgE production.
