Trends in Immunology
Volume 33, Issue 10, October 2012, Pages 505-512
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Review
Defining the human T helper 17 cell phenotype

https://doi.org/10.1016/j.it.2012.05.004Get rights and content

T helper (Th) 17 cells represent a third effector arm of CD4 T cells and complement the function of the Th1 and Th2 cell lineages. Here, we provide an overview of the transcription factors, cytokines, chemokines, and cytokine and chemokine receptors that characterize the Th17 cell phenotype. Data relevant for human Th17 cells are emphasized, with a focus on the function of two markers that have recently been associated with human Th17 cells, CD161 and interleukin-4-induced gene 1 (IL4I1). Also considered is the basis of Th17 cell plasticity towards the Th1 lineage, and we suggest that this plasticity together with the limited expansion of Th17 cells in response to T cell receptor (TCR) triggering accounts for the rarity of human Th17 cells in inflamed tissues.

Section snippets

Beyond the Th cell Th1/Th2 paradigm

Activated CD4+ Th cells can be subdivided into lineages based on their cytokine secretion, transcription factor expression, and immunological function. Initially, CD4+ Th cells were thought of as having one of two possible fates: Th1 or Th2 cells. Th1 cells express the transcription factor T-bet, secrete interferon (IFN)-γ and protect the host against intracellular infections. Th2 cells express GATA binding protein 3 (GATA-3), secrete IL-4, IL-5 and IL-13, and mediate host defense against

Cytokines and chemokines produced by Th17 cells

Both murine and human Th17 cells produce IL-17A and IL-17F, and these cytokines have been used to define this subset 3, 4, 5. IL-17A and IL-17F are similar in their biological activity, target both immune and nonimmune cell types (Figure 1), and play an important role in the inflammatory response. IL-17A induces chemokine CXC ligand (CXCL)8 production from epithelial cells, endothelial cells, fibroblasts and macrophages, leading to recruitment of neutrophils. In addition, several cell types in

Th17 cell transcription factors

Murine Th17 cells express the transcription factor retinoic acid orphan receptor (ROR)γt (Rorc), but not T-bet or GATA-3 25, 26. RORγt is a master regulator of Th17 cell differentiation, and Rorc deletion dramatically reduces the number of Th17 cells in mutant mice as a result of impaired Th17 cell differentiation [25]. Murine Th17 cells also express Rora. Deletion of Rora alone has little effect on IL-17 production, however, deficiency of both Rora and Rorc completely abolishes Th17

Human Th17 cell cytokine and chemokine receptors

Murine Th17 cells express several cytokine receptors, most of which were identified based on the ability of the corresponding cytokine to induce Th17 cell differentiation. These include the IL-6 receptor (IL-6R), transforming growth factor (TGF)-β receptor, IL-23R, IL-21R, and IL-1R. Differentiation of naïve murine Th cells into Th17 cells was initially suggested to result from the combined activity of IL-6 and TGF-β in vitro 36, 37, 38. IL-23 induces expansion and/or maintain survival of Th17

Markers associated specifically with human Th17 cells

The factors characteristic of the Th17 cell phenotype discussed so far are relevant for both human and mouse Th17 cells. Recent work has identified expression of CD161 and IL4I1 specifically in human Th17 cells.

Concluding remarks

Several features of murine Th17 that were described early on have since been challenged by human studies, and also in more recent work on mouse Th17 cells. For example, the requirement for TGF-β for in vitro development of Th17 cells is now controversial. It is also emerging that Th17 cells are plastic, with the ability to shift to Th1-like cells at inflamed sites. Expression of the IL-12Rβ2 chain on the cell surface contributes to Th17 cell plasticity 16, 51, which allows Th17 cells to

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