Interleukin-17 (IL-17)-producing T helper (T_H17) cells are the latest T-cell subset to take centre stage in immunology, with many hundreds of studies in mice characterizing their role as effector cells in various settings, including inflammation, autoimmunity and immune defence. However, much less is known about their identity and properties in humans. Now, Acosta-Rodriguez et al. provide the first detailed characterization of human T_H17 cells and allude to their distinct migratory capacity and antigenic specificity.

The selective expression of chemokine receptors, a feature that allows different effector-cell subsets to home to different sites, can be used to distinguish subsets of memory T cells. So, Acosta-Rodriguez et al. sorted T cells from human peripheral blood according to their expression of CCR7 (CC-chemokine receptor 7), CCR6, CCR4 and CXCR3 (CXC-chemokine receptor 3) and assayed for cytokine production in the ensuing memory CD4⁺ T-cell subsets. T_H17 cells were detected in both CCR7⁺ (central memory) and CCR7^- (effector memory) CD4⁺ T-cell subsets. As expected, interferon- (IFN)-producing T_H1 cells were enriched in the CXCR3⁺ population. Surprisingly, however, the expression of CCR6, which mediates homing to the skin and mucosal tissues, precisely identified all T_H17 cells. But the CCR6⁺ subset also contained T_H1 cells and a subset of cells that produced both IL-17 and IFN. To discriminate between T_H17 and T_H1 cells in the CCR6⁺ subset, the authors found that within the CCR6⁺ subset CCR4 expression corresponded to T_H17 cells and CXCR3 expression corresponded to T_H1 cells (and the subset of T cells producing both IFN and IL-17). These CCR6⁺CCR4⁺ T_H17-cell and CCR6⁺CXCR3⁺ T_H1-cell phenotypes were shown to be stable even after stimulation in vitro.

To further characterize these T_H17 cells, the authors turned their attention to the transcription factor RORt (retinoic-acid-receptor-related orphan receptor-t), which is known to be required for the differentiation of mouse T_H17 cells. The levels of mRNA encoding the human orthologue of RORt (RORC) were measured in each memory T-cell subset. Accordingly, RORC mRNA expression was restricted to the CCR6⁺CCR4⁺ T_H17-cell subset, whereas expression of the T_H1-cell-associated transcription factor T-bet was confined to the CXCR3⁺ T_H1-cell subsets.

Next, the authors explored whether antigen-specific T cells were differentially distributed between the subsets. Remarkably, they found that memory T cells that were specific for Candida albicans were mainly found in the CCR6⁺CCR4⁺ T_H17-cell subset, whereas cells specific for Mycobacterium tuberculosis were present in the CCR6⁺CXCR3⁺ T_H1-cell subset.

Because C. albicans can exist in two forms — a yeast form or a hyphal form — the authors tested whether this might be responsible for a polarized response. Indeed, they found that culturing naive human T cells and monocytes with CD3-specific antibody in the presence of the hyphal form promoted differentiation into T_H17 cells, whereas the yeast form promoted T_H1-cell differentiation. This polarization correlated with cytokine production by monocyte-derived dendritic cells in co-cultures: the yeast form induced mostly IL-12 production (a T_H1-cell-inducing cytokine), whereas the hyphal form induced only IL-23 production, which is associated with T_H17-cell differentiation.

So, these findings provide a functional link between microbial products, T_H-cell differentiation and homing in response to fungal antigens, and open up exciting avenues for future study of T_H17 cells in humans.

Author: Lucy Bird - Copyright © 2007 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission