ICOS has been linked to the development of TFH cells and TH17 cells, but it was previously unclear in which stage of their developmental pathways ICOS might act. To explore this issue, Kuchroo and colleagues used Icos−/− mice. Consistent with earlier reports that ICOS is required for TFH-cell development, preliminary in vitro experiments revealed that only a few TFH cells developed in Icos−/− mice. By contrast, the authors observed that there was no difference in the ability of naive CD4+ T cells from wild-type and Icos−/− mice to differentiate into TH17 cells in the presence of IL-6 and transforming growth factor-β (TGFβ). TH17-cell development could also be efficiently induced in vivo in Icos−/− mice. However, further analysis indicated that Icos−/− CD4+ T-cell populations that were expanded in vitro in the presence of IL-23 produced less IL-17 than wild-type T cells. This defect in IL-17 production was observed even when Icos−/− T cells were cultured with IL-6 and TGFβ prior to the addition of IL-23, which suggests that ICOS was required for the expansion of TH17-cell populations in response to IL-23. Indeed, this unresponsiveness to IL-23 was found to be due to reduced expression of the IL-23 receptor (IL-23R) by Icos−/− T cells.
The previous finding that both TH17 cells and TFH cells produce IL-21, which is thought to amplify TH17-cell responses by upregulating the expression of IL-17 and IL-23R, led the authors to investigate the functional relationship between these two T-cell subsets. Unexpectedly, they observed that, similarly to TH17 cells, many TFH cells also produced IL-17 and expressed IL-23R. Moreover, the ability of TFH cells to produce IL-17 was increased in the presence of IL-23. Analysis of the few TFH cells that developed in Icos−/− mice showed that they were significantly impaired in their ability to produce IL-17 and IL-21, even in the presence of IL-23.
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