Autosomal Dominant-Hyper-IgE Syndrome patients contain pre-Th17-cells that are activated by opportunistic pathogens to produce IL-10
Authors: Moschetti Giorgia , Vasco Chiara , Clemente Francesca , Larghi Paola , Maioli Sara , Scarpa Edoardo , Carelli Elena , Pulvirenti Nadia , Sarnicola Maria Lucia , Crosti Mariacristina , Bel Imam Manal , van de Veen Willem , Rizzello Loris , Abrignani Sergio , Baselli Lucia A. , Dellepiane Rosa Maria , Carrabba Maria , Fabio Giovanna , Geginat Jens 
Published: August 2024

STAT3 is required for Th17-cell differentiation, and dominant-negative STAT3 mutations cause Autosomal Dominant-Hyper-IgE Syndrome (AD-HIES), which is characterized by a lack of Th17-cells and recurrent infections with opportunistic extracellular pathogens. T-cell responses to opportunistic pathogens in AD-HIES patients have however not been characterized. We previously identified an enigmatic population of IL-10 producing CCR6+Th-cells that were largely non-polarised and lacked other subset-defining differentiation markers (“CCR6single-positive(SP)”). Here we report that CCR6SPT-cells are central memory T-cells (TCM) that expressed the stemness-associated transcription factors LEF1 and TCF7, but also RORγt, the lineage-defining transcription factor of Th17-cells. Non-polarized CCR6SPT-cells differentiated spontaneously to Th17-cells upon TCR stimulation, indicating that they were pre-committed to a Th17 fate. Spontaneous Th17 differentiation was promoted by an autocrine loop of STAT3-activating cytokines and inhibited by IL-4. IL-12 induced in addition IFN-γ, and consequently differentiation to Th1/17-cells. CCR6+T-cells were strongly reduced in AD-HIES and Th17- and Tfh17-cells were hardly detectable. However, the residual CCR6+T-cells contained Th1/17- and CCR6SPT-cells that proliferatedin vivo. They produced high amounts of IL-10, indicating that, unexpectedly, IL-10 production by human T-cells is STAT3-independentin vivo. Intriguingly, opportunistic pathogens selectively activated CCR6+T-cells in AD-HIES patients to produce IL-10. Opportunistic bacteria and Mycobacterium tuberculosis induced in addition IL-2 and IFN-γ. We conclude that Th17 differentiation is not completely impaired in the absence of STAT3 signalling but arrested at an early stage of CCR6+TCM. These pre-Th17-cells produce IL-10 and require STAT3 to differentiate to Th17-cells and to fight extracellular pathogens but could directly generate Th1/17-cells to contain intracellular bacteria.

Significance

AD-HIES patients have impaired STAT3 signalling, lack consequently Th17-cells and experience recurrent infections with opportunistic extracellular pathogens. These patients were key to the dogma that Th17-cells control extracellular pathogens, but T-cell responses to these pathogens have surprisingly never been analyzed. Here, we report that Th17 differentiation in response to opportunistic extracellular pathogens in the absence of STAT3 signalling is arrested at an early stage of pre-Th17-cells that produce high levels of IL-10. These otherwise non-polarised T-cells acquired IFN-gamma production with IL-12 that could enable them to contain intracellular bacteria. These surprising findings demonstrates that Th17 differentiation is not completely blocked in the absence of STAT3 signalling, and that IL-10 production by human T-cells is STAT3-independentin vivo.