Th9 mystery: Is it finally solved?

In the recent article by Kaplan group, the authors have dissected the mechanisms by which Th9 cells develop. The Th9 cells are described as CD4+IL9+IL10+ T cells by Stockinger and Kuchroo groups in nature Immunology 2008. Previously, immunologists felt that IL9 secretion is part of Th2 function. IL9 is an important cytokine secreted by Th2 cells which has an effect on mast cell function. However, there is ambiguity in secretion of IL9 by Th2 polarised cells.
Kaplan group have identified PU.1 as the transcription factor that drives Th9 polarisation. PU.1 is expressed by sub-population of Th2 populations expressing low IL4. In addition, PU.1 deficient cells secrete less IL9 compared to the cells that have PU.1. The authors also show that IL10 secretion is not characteristic feature of Th9 cells as reported by Stockinger and Kuchroo groups before. The authors identify the chromatin modifications on il9 locus  by PU.1 by ChIP assays. Finally, by analyzing allergic patients and also the allergic asthma model, the authors show the obligatory role of  IL9 and PU.1 in the manifestation of asthma.
By this study, the authors have made the knowledge of Th cells more complex. The T cells are now known to be plastic. The regulatory T cells and the Th17 cells share common but contrasting developmental pathways. Similiarly, Th2 cells develop in presence of IL4 while the Th9 cells need IL4 and TGFb1 for their development.Also, PU.1 and GATA-3 interact with each other similar to FoxP3 and RORg which answers the plasticity among the Th subsets.These raise important issues about the role of Th cells in innate immune responses where there is need for spontaneous immune responses.

Recommended reading:
1. H. C. Chang, S. Sehra, R. Goswami, W. Yao, Q. Yu, G. L. Stritesky, R. Jabeen, C. McKinley, A. N. Ahyi, L. Han, E. T. Nguyen, M. J. Robertson, N. B. Perumal, R. S. Tepper, S. L. Nutt, and M. H. Kaplan. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat.Immunol., 2010.

2.V. Dardalhon, A. Awasthi, H. Kwon, G. Galileos, W. Gao, R. A. Sobel, M. Mitsdoerffer, T. B. Strom, W. Elyaman, I. C. Ho, S. Khoury, M. Oukka, and V. K. Kuchroo. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat.Immunol. 9 (12):1347-1355, 2008. 

3.W. Elyaman, E. M. Bradshaw, C. Uyttenhove, V. Dardalhon, A. Awasthi, J. Imitola, E. Bettelli, M. Oukka, Snick J. Van, J. C. Renauld, V. K. Kuchroo, and S. J. Khoury. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc.Natl.Acad.Sci.U.S.A 106 (31):12885-12890, 2009. 

4. E. E. Forbes, K. Groschwitz, J. P. Abonia, E. B. Brandt, E. Cohen, C. Blanchard, R. Ahrens, L. Seidu, A. McKenzie, R. Strait, F. D. Finkelman, P. S. Foster, K. I. Matthaei, M. E. Rothenberg, and S. P. Hogan. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J.Exp.Med. 205 (4):897-913, 2008.