At sites of inflammation, certain regulatory Tcells (Treg cells) can undergo rapid reprogramming into helper-like cells without loss of the transcription factor Foxp3. We show that reprogramming is controlled by downregulation of the transcription factor Eos (Ikzf4), an obligate corepressor for Foxp3. Reprogramming was restricted to a specific subset of "Eos-labile" Treg cells that was present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive Tcells. Downregulation of Eos required the proinflammatory cytokine interleukin-6 (IL-6), and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eosand prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains acommitted subset of Treg cells capable of rapid conversion into biologically important helper cells. •A subset of Treg cells shows labile expression of the corepressor Eos•These Treg cells can reprogram into helper cells without losing Foxp3•Eos-labile Treg cells are constitutively present in thymus, lymph nodes, and spleen•Reprogrammed Treg cells can help support priming of effector Tcells to new antigen.
|Original language||English (US)|
|Number of pages||15|
|State||Published - May 23 2013|
Bibliographical noteFunding Information:
The authors thank Anita Sharma, Judy Gregory, Joyce Wilson, and Jeanene Pihkala for expert technical assistance. Supported by National Institutes of Health grants CA103320, CA096651, CA112431 (to D.H.M.); HD41187, AI083005, AI063402 (to A.L.M.); and CA72669, HL56067, AI34495 (to B.R.B.); and an Immunotherapy Discovery Institute seed grant (to H.S.). H.S. is a Georgia Cancer Coalition Distinguished Cancer Scientist. D.H.M., A.L.M., and B.R.B. have intellectual property interests in the therapeutic use of IDO and IDO inhibitors. D.H.M. and A.L.M. receive consulting income and research support from NewLink Genetics, which holds a license to develop the IDO technology for clinical trials.