Spotting the troublemakers

Credit: NPG

T helper 17 (T_H17) cells produce interleukin-17 (IL-17) and are thought to promote various inflammatory conditions, including Crohn's disease. However, not all T_H17 cells are pathogenic, and some have beneficial immunoregulatory functions. As such, there is interest in developing therapeutics that specifically target disease-promoting T_H17 cells. A recent study by Ramesh et al. now describes a method for distinguishing pathogenic from non-pathogenic T_H17 cells in humans.

Recent studies in mice have shown that pathogenic T_H17 cells produce interferon-γ (IFNγ) and express high levels of the IL-23 receptor (IL-23R). Previous work has also suggested that human memory T_H17 cells can be divided into two main subsets on the basis of chemokine receptor expression — CCR6⁺CCR4^hi T_H17 cells express IL-17, but not IFNγ, whereas CCR6⁺CXCR3^hi T_H17 cells express both IL-17 and IFNγ. Consistent with this, Ramesh et al. identified similar T_H17 cell populations in blood from healthy adults. Compared with CCR6⁺CCR4^hi T_H17 cells, CCR6⁺CXCR3^hi T_H17 cells produced lower levels of IL-17 but expressed higher levels of mRNAs encoding IL-23R and other pro-inflammatory mediators, such as CC-chemokine ligand 3 (CCL3), CCL4, CCL5 and granzyme B. By contrast, CCR6⁺CCR4^hi T_H17 cells expressed higher levels of mRNAs encoding anti-inflammatory mediators, such as IL-10 and the IL-1R antagonist protein. However, despite these differences in IL-23R expression, both populations showed a similar, weak response to IL-23-mediated stimulation in vitro. The authors therefore hypothesized that potentially pathogenic IL-23-responsive T_H17 cells represent only a minor subset of the CCR6⁺CXCR3^hi T cell population.

a method for identifying potentially pathogenic T_H17 cells in humans

In agreement with this, they were able to identify a subpopulation of CCR6⁺CXCR3^hi T cells that was enriched for pathogenic characteristics, including enhanced responsiveness to IL-23, as determined by increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) and increased production of IL-17. These cells specifically expressed multidrug resistance protein 1 (MDR1; also known as P-glycoprotein), which is a membrane transporter that can promote the efflux of a broad range of substrates. Notably, the authors found that MDR1⁺ memory T cells were enriched in biopsy samples from the inflamed gut of patients with Crohn's disease compared with either peripheral blood from the patients or biopsy samples from non-inflamed gut. Furthermore, MDR1⁺ T cells from inflamed gut tissue expressed genes associated with pathogenic T_H17 cell activity, whereas MDR1⁻ T cells from the same biopsy samples expressed genes associated with non-pathogenic T_H17 cells.

Finally, in ex vivo culture experiments, the authors showed that MDR1⁺ T_H17 cells from healthy humans are resistant to the immunosuppressive effects of glucocorticoids. Strikingly, treatment with glucocorticoids actually led to the enrichment of MDR1⁺ T_H17 cells within mixed T cell cultures. Notably, patients with Crohn's disease often develop steroid-resistant disease, but the reasons for this have not been clear.

Taken together, these findings have important clinical implications as they not only describe a method for identifying potentially pathogenic T_H17 cells in humans but also suggest a possible mechanism for why certain patients with Crohn's disease do not respond to glucocorticoid therapy.

This article is modified from the original in Nature Rev. Immunol. (http://dx.doi.org/10.1038/nri3610).