Staphylococcus aureus-derived factors promote human Th9 cell polarization and enhance a transcriptional program associated with allergic inflammation.

T helper (Th) 9 cells, characterized by robust secretion of IL-9, have been increasingly associated with allergic diseases. However, whether and how Th9 cells are modulated by environmental stimuli remains poorly understood. In this study, we show that in vitro exposure of human PBMCs or isolated CD4 T-cells to Staphylococcus (S.) aureus-derived factors, including its toxins, potently enhances Th9 cell frequency and IL-9 secretion. Furthermore, as revealed by RNA sequencing analysis, S. aureus increases the expression of Th9-promoting factors at the transcriptional level, such as FOXO1, miR-155, and TNFRSF4. The addition of retinoic acid (RA) dampens the Th9 responses promoted by S. aureus and substantially changes the transcriptional program induced by this bacterium, while also altering the expression of genes associated with allergic inflammation. Together, our results demonstrate a strong influence of microbial and dietary factors on Th9 cell polarization, which may be important in the context of allergy development and treatment.

Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity.

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.

Th9 cells in allergic diseases: A role for the microbiota?

Since their discovery about 10 years ago, Th9 cells have been increasingly linked to allergic pathologies. Within this review, we summarize the current knowledge on associations between Th9 cells and allergic diseases and acknowledge Th9 cells as important targets in future treatment of allergic diseases. However, until today, it is not fully understood how these Th9 cell responses are modulated. We describe current literature suggesting that these Th9 cell responses might be stimulated by microbial species such as Staphylococcus aureus and Candida albicans, while on the other hand, microbial and dietary compounds such as retinoic acid (RA), butyrate and vitamin D show suppressive capacity on allergy-related Th9 responses. By reviewing this recent research, we provide new insights into the modulating capacity of the microbiota on Th9 cell responses. Consequently, microbial and dietary factors may be used as innovative tools to target Th9 cells in the treatment of allergic diseases. However, further research is needed to elucidate the mechanisms behind these interactions in order to translate this knowledge into clinical allergy settings.