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

Abstract

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.

Helper T cell immunity in humans with inherited CD4 deficiency

“…Specifically, patients CD3 + CD8 − T cells exhibited reduced IL-2 signaling as well as mild cell-intrinsic impairments in differentiating into T H 1-type, T H 17-type, and IL-9 + effector cells. Human CD4 + T cells that commit to a T H 1 or T H 17 fate or that produce IL-9 have important roles in host defense against different infections, particularly those caused by fungal and staphylococcal species ( Badolati et al, 2023 ; Bröker et al, 2016 ; Brown et al, 2015 ; McDonald, 2012 ; Puel et al, 2012 ; van de Veerdonk and Netea, 2010 ; Zielinski et al, 2012 ). While these cells have not been directly implicated in protection against HPV, our findings indicate that further functional analyses of the roles of specialized subsets of human CD4 + T cells in protective responses are warranted.…”

T helper cell subsets: diversification of the field

“…These cells are derived from naïve T-cell precursors via TGF-β signaling in the presence of IL-4 or "switch" at the effector cell level to IL-9-only producing cells if exposed to TGF-β in mice [8]. Staphylococcus aureus derived enterotoxin B has also been reported to drive Th9 cell differentiation in both mice and humans, stressing the importance of microbial factors for the regulation of these cells [36,37].…”

IL-24 is the key effector of Th9 cell-mediated tumor immunotherapy

“… 31 Previous studies show that Th9 cells also express IL-24. 5 , 32 , 33 , 34 However, the role of IL-24 in Th9 cell-mediated antitumor activity remains unclear.…”