Several studies in mice have suggested that not only did Tfh cells produce IL-21, but IL-21 could also drive IL-21 production and Tfh cell differentiation.8,42,56,57 Subsequent studies, however, showed that disruption of IL-21 signals had little or no effect on Tfh cell development.35,58–62 IL-6 has also been shown to induce IL-21 production and Tfh cell generation.42,57,63 However, once again, while some studies have shown a decrease in Tfh cell generation in the absence of IL-6,42 others have failed to see any defect in the absence of IL-6.35,62,63 These discrepancies probably reflect a level of redundancy in the signals required for

generating Selleck Navitoclax Tfh cells. Indeed, both IL-6 and IL-21 signal through signal transducer and activator of transcription 3 (STAT3) and a recent paper by Eto et al.62 demonstrated that, although the absence of only one of these

cytokines did not affect Tfh cell numbers, the combined absence of IL-6 and IL-21 did result in a significant decrease. This decrease, however, was not complete, and a substantial number of Tfh cells could still be found. In this light it is interesting to note that a recent study demonstrated that another STAT3-activating cytokine, IL-27, can also increase IL-21 production and Tfh cell generation.64 Thus, the ability of all three of these cytokines to activate STAT3 contributes to a high level of redundancy in their requirement for Tfh cell generation. However, CD4+ CXCR5+ cells can still be identified even in the absence aminophylline of STAT3 itself, suggesting that it may not be absolutely required for the generation of Tfh cells,42,63 RAD001 nmr indicating that an even greater level of redundancy

exists. However, in the absence of STAT3 these CD4+ cells were very poor at supporting B cell responses, suggesting that STAT3 may be more important for the functional ability of Tfh cells even if it is not required for the cell surface expression of Tfh-associated molecules. The role of cytokines in inducing B cell helper function from naive human CD4+ T cells differs from that of mice in that it has been shown to largely involve IL-12, and to a lesser extent IL-6, IL-21 and IL-23.8,65 IL-12 induced the differentiation of cells expressing IL-21, CXCR5, ICOS and Bcl-6 that facilitated antibody production by B cells in vitro.8,65 Interestingly, several studies have found little effect of IL-12 on the production of IL-21 by murine CD4+ T cells,42,57,66 although another paper observed a significant proportion of IL-21 secreting cells in response to IL-12.62 These results suggest that different cytokine pathways may be involved in the generation of human versus murine Tfh cells. The key function of Tfh cells is to provide help to B cells to support their activation, expansion and differentiation and the formation of the GC. Several features of Tfh cells enable them to carry out these functions.