Autosomal Dominant-Hyper-IgE Syndrome patients contain pre-Th17-cells that are activated by opportunistic pathogens to produce IL-10

Moschetti, G.; Vasco, C.; Clemente, F.; Larghi, P.; Maioli, S.; Scarpa, E.; Carelli, E.; Pulvirenti, N.; Sarnicola, M. L.; Crosti, M.; Bel Imam, M.; van de Veen, W.; Rizzello, L.; Abrignani, S.; Baselli, L. A.; Dellepiane, R. M.; Carrabba, M.; Fabio, G.; Geginat, J.

doi:10.1101/2024.08.01.606136

bioRxiv · 10.1101/2024.08.01.606136

Autosomal Dominant-Hyper-IgE Syndrome patients contain pre-Th17-cells that are activated by opportunistic pathogens to produce IL-10

Moschetti, G.·Vasco, C.·Clemente, F.·Larghi, P.·Maioli, S.·Scarpa, E.·Carelli, E.·Pulvirenti, N.·Sarnicola, M. L.·Crosti, M.·Bel Imam, M.·van de Veen, W.·Rizzello, L.·Abrignani, S.·Baselli, L. A.·Dellepiane, R. M.·Carrabba, M.·Fabio, G.·Geginat, J.

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Abstract

BackgroundAutosomal 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. MethodsHuman 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. ResultsCCR6+Th-cells that lacked subset-defining differentiation markers were mostly non-polarised central memory T-cells (TCM) that produced IL-10 and expressed ROR{gamma}t. 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+TCM 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. ConclusionsTh17 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.

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Moschetti, G., Vasco, C., Clemente, F., Larghi, P., Maioli, S., Scarpa, E., Carelli, E., Pulvirenti, N., Sarnicola, M. L., Crosti, M., Bel Imam, M., van de Veen, W., Rizzello, L., Abrignani, S., Baselli, L. A., Dellepiane, R. M., Carrabba, M., Fabio, G., Geginat, J.. 2024-08-04. Autosomal Dominant-Hyper-IgE Syndrome patients contain pre-Th17-cells that are activated by opportunistic pathogens to produce IL-10. https://doi.org/10.1101/2024.08.01.606136

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