Foxp3+ regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8+ T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4+ cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8+ T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8+ T cell responses.
Bibliographical noteFunding Information:
We thank A. Sharma, J. Gregory, and J. Wilson for expert technical assistance; J. Pikhala for cell sorting; W. King for GFP-YFP analysis by FACS; A. Rudensky for providing Foxp3 GFP mice; D. Ron for providing Eif2ak4 −/− mice; and S. Akira for the use of Myd88 −/− mice. Supported by NIH grants CA103320, CA096651, and CA112431 (to D.H.M.) and HD41187 and AI063402 (to A.L.M.). D.H.M., A.L.M., and M.D.S. 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, Inc., which holds a license to develop the technology for clinical trials.
Copyright 2011 Elsevier B.V., All rights reserved.