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Important New Features and Glucocorticoid-Resistance of Pro-Inflammatory Th17 Cells

Guillain-Barré Syndrome

A recent study by Radha Ramesh and colleagues, published in the Journal of Experimental Medicine indicates that the expression of the multi-drug transporter MDR1 (also known as P-glycoprotein [P-gp] and ABCB1) is a marker that defines the pro-inflammatory nature of T helper (Th)17 cells.

The Th17 cells are major players in inflammatory/autoimmune conditions, but not all Th17 cells are inflammatory. In mice, a subset of nonpathogenic Th17 cells develop in the absence of interleukin (IL)-23/IL-23R; produce IL-17A along with IL-10; and may exert anti-inflammatory effects.

Conversely, data in humans indicate that in response to IL-23, memory lymphocytes expand into a Th17 phenotype, with a subpopulation of cells simultaneously expressing IFN-γ and IL-17. Importantly, it appears that the co-expression of IL-17A and IFN-γ is a hallmark of T cells isolated from inflamed tissues. In addition, the cellular responses to IL-23 and the IL-23R expression levels may distinguish between pro- and anti-inflammatory Th17 cells.

Of note, the study of Rameshet al. demonstrates that IL-23R expression does not mark the ‘canonical’ Th17; it is increased, however, in CCR6+ Th17 subsets that display Th1-like properties (i.e., Th17.1 cells expressing IFN-γ and CXCR3). Importantly, the authors of this study show that both high-level IL-23R expression and marked functional responses to IL-23 stimulation are confined to a subset of Th17.1 cells that expresses the multi-drug transporter MDR1/P-gp.

Furthermore, the study also uncovered that MDR1+ Th17.1 cells are highly sensitive to IL-23 stimulation, are increased within the gut tissue of Crohn’s disease patients, and are resistant to the anti-inflammatory actions of several glucocorticoids.

According to the authors, these features reveal the pathogenic nature of these cells. They may be relevant to several inflammatory and autoimmune conditions, and the development of new therapeutic approaches for immune-mediated diseases.

Source: J Exp Med 2014, 211:89-104. doi: 10.1084/jem.20130301. Epub 2014 Jan 6.
Read More: Journal of Experimental Medicine

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