Discovery and initial characterization of Th9 cells: the early years

The launch of the Th1/Th2 concept represented a decisive breakthrough concerning our understanding of how very diverse immune reactions can be regulated by functionally different T helper subpopulations via the secretion of different panels of cytokines. In this context, IL-9 was identified to be produced by T helper cell lines in addition to Th2 cytokines IL-4 and IL-5. Detailed analyses revealed that IL-9 production of mouse CD4⁺ T helper cells was dependent on a combination of IL-2, IL-4, and TGF-β. Roughly a decade later, it was found that TGF-β can also induce the development of CD4⁺ Treg cells. This finding engendered a series of studies on the central role of TGF-β for cytokine-mediated T helper cell differentiation which elucidated that IL-4 curbed the Treg cell-promoting effect of TGF-β while TGF-β impaired the Th2-promoting capacity of IL-4. Instead, TGF-β in combination with IL-4 induced the development of CD4⁺ T helper cells that preferentially produced IL-9 and that were different from Th2 cells which originally were thought to be the main source of IL-9. In addition, adoptive transfer of such IL-9-producing CD4⁺ T helper cells was shown to cause the development of colitis and peripheral neuritis. Hence, the unique cytokine expression pattern in combination with the inflammatory in vivo phenotype led to the designation of Th9 cells as a new CD4⁺ T helper subpopulation.