De novo generation of IL-17-producing T cells

The mechanism involved in the de novo differentiation of interleukin-17 (IL-17)-producing T cells from naive CD4⁺ T cells is not fully understood, but it has been suggested that IL-23 might be involved. Now, new research published in Immunity highlights a pivotal role for transforming growth factor-β (TGFβ), together with the pro-inflammatory cytokine IL-6, in the generation of these cells.

The naturally occurring CD4⁺CD25⁺ regulatory T (T_Reg)-cell subset — which can prevent immune pathology through the suppression of potentially pathogenic T cells — suppress proliferation and IL-2 production by naive CD4⁺ T cells in vitro. However, Stockinger and colleagues show that in the presence of an inflammatory stimulus, such as lipopolysaccharide (LPS), T_Reg cells do not suppress T-cell proliferation but still retain the ability to suppress the production of IL-2 and also interferon-γ (IFNγ). Interestingly, co-culture of T_Reg cells with naive CD4⁺ T cells, in the presence of dendritic cells (DCs) and LPS, results in the induction of IL-17-producing T cells.

TGFβ, an immunosuppressive cytokine that is produced by various cell types including T_Reg cells, was identified as the key component in this differentiation process. Blocking TGFβ, but not the T_Reg-cell-associated cytokine IL-10, with neutralizing antibodies suppressed the generation of IL-17-producing T cells. The T_Reg cells could also be replaced in the co-culture by addition of TGFβ, highlighting the crucial role of this cytokine in the differentiation of IL-7-producing T cells.

This study also showed that in addition to TGFβ, a DC-derived factor is required, as the generation of IL-17-producing T cells did not occur in the absence of DCs. The authors identified the cytokine IL-6 as this essential mediator. Blocking of IL-6 suppressed the development of IL-17-producing T cells, whereas tumour-necrosis factor (TNF) and IL-1β further augmented this differentiation. Interestingly, inhibition of IL-23 did not affect the differentiation of these cells, indicating that this cytokine probably does not have a role in the de novo generation of IL-17-producing T cells, although it is an important factor for their survival and expansion.

Co-culture of naive CD4⁺ T cells with DCs and LPS in the presence of antibodies specific for the T helper 1 (T_H1)-associated cytokines IL-12, IL-23 and IFNγ and the T_H2-associated cytokine IL-4, resulted in the differentiation of IL-17-producing T cells. Inclusion of TGFβ-specific antibodies inhibited this differentiation, indicating that, in addition to TGFβ produced by T_Reg cells, LPS-stimulated DCs can produce TGFβ, albeit in amounts that cannot support IL-17-producing T-cell differentiation without further blockade of cytokines that promote the differentiation of the other T-cell subsets.

Therefore, TGFβ, together with IL-6, is essential for the de novo differentiation of IL-17-producing T cells from naive CD4⁺ T cells. It seems that, in addition to the suppressive role of TGFβ on T_H1, and T_H2-cell differentiation, this cytokine might also have a more direct role in the differentiation of IL-17-producing T cells. So, this study shows that a unique balance of pro- and anti-inflammatory cytokines is necessary for the de novo generation of IL-17-producing T cells.