Induction and effector functions of T(H)17 cells

Abstract

T helper (T(H)) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered T(H)17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that T(H)17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (T(reg)) cells, which prevent tissue inflammation and mediate self-tolerance.

Figure 1 |. Subsets of T helper cells.

Depending on the cytokine milieu present at the time of the initial engagement of their T-cell receptor and costimulatory receptors in the peripheral immune compartment, naive CD4¹ T cells can differentiate into various subsets of T helper cells (T_H1, T_H2 and T_H17). However, in the presence of TGF-β, naive T cells convert into FOXP3-expressing induced T_reg (iT_reg) cells. For each T helper cell differentiation programme, specific transcription factors have been identified as master regulators (T-bet, GATA3 and ROR-γt). Terminally differentiated T helper cells are characterized by a specific combination of effector cytokines that orchestrate specific and distinct effector functions of the adaptive immune system.

Figure 2 |. Steps in the differentiation of T_H17 cells.

Different factors control the initial differentiation of T_H17 cells from naive T cells, the amplification of T_H17 precursor cells, and finally the stabilization and effector phenotype of T_H17 cells. Whereas TGF-β together with IL-6 are the differentiation factors for T_H17 cells, IL-21, which is produced by T_H17 cells themselves, acts in a positive feedback loop to increase the frequency of T_H17 cells. STAT3 is the essential signalling molecule for the differentiation of T_H17 cells because the induction of IL-21 is absolutely dependent on STAT3, and STAT3 is also critical in the signal transduction cascades of IL-6, IL-21 and IL-23 receptors. IL-23 expands and stabilizes T_H17 cells to produce their effector cytokines IL-17, IL-17F and IL-22.

Figure 3 |. The developmental pathways of T_H17 cells and FOXP3⁺ T_reg cells require TGF-β signalling and are reciprocally regulated.

TGF-β is ubiquitous although its most relevant source in regulating immune reactions is still unclear. Other factors such as retinoic acid or cytokines such as IL-6, IL-1, IL-23 or IL-27 are provided by cells of the innate immune system (immature or activated dendritic cells (DCs), respectively) and dictate whether a naive T cell (TC) develops into a FOXP3⁺ T_reg cell, a T_H17 cell or an IL-10-secreting T cell of the Tr-1 phenotype. IL-6R, IL-6 receptor; IL-21R, IL-21 receptor; IL-23R, IL-23 receptor; RAR, retinoic acid receptor; TGF-βR, TGF-β receptor; WSX-1, IL-27 receptor).

Figure 4 |. Effects of TGF-β in shaping the transcriptional programme of developing T helper cell subsets.

a, IL-6 and TGF-β independently induce specific gene expression programmes in T cells. However, when both cytokines act in concert, an essentially novel and distinct gene expression programme is induced resulting in a qualitatively different outcome such as the T_H17 transcriptional programme (IL-17, IL-17F and IL-22). b, In contrast, when TGF-β acts in combination with cytokines such as IL-27, IFN-γ expression is scaled down and IL-10 expression is increased resulting in a Tr-1-like phenotype.