| First Author | O'Connor RA | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 12 | Pages | 7235-43 |
| PubMed ID | 21084662 | Mgi Jnum | J:167459 |
| Mgi Id | MGI:4868313 | Doi | 10.4049/jimmunol.1001551 |
| Citation | O'Connor RA, et al. (2010) Myelin-reactive, TGF-beta-induced regulatory T cells can be programmed to develop Th1-like effector function but remain less proinflammatory than myelin-reactive Th1 effectors and can suppress pathogenic T cell clonal expansion in vivo. J Immunol 185(12):7235-43 |
| abstractText | Interest in the use of regulatory T cells (Tregs) as cellular therapeutics has been tempered by reports of naturally occurring Tregs losing Foxp3 expression and producing IL-17, raising concerns over a switch to pathogenic function under inflammatory conditions in vivo. TGF-beta-induced Tregs (inducible Tregs [iTregs]), generated in large numbers in response to disease-relevant Ags, represent the most amenable source of therapeutic Tregs. Using Foxp3-reporter T cells recognizing myelin basic protein (MBP), we investigated the capacity of iTregs to produce effector-associated cytokines under proinflammatory cytokine conditions in vitro and whether this translated into proinflammatory function in vivo. In contrast with naturally occurring Tregs, iTregs resisted conversion to an IL-17-producing phenotype but were able to express T-bet and to produce IFN-gamma. iTregs initiated their T-bet expression during their in vitro induction, and this was dependent on exposure to IFN-gamma. IL-12 reignited iTreg expression of T-bet and further promoted iTreg production of IFN-gamma upon secondary stimulation. Despite losing Foxp3 expression and expressing both T-bet and IFN-gamma, MBP-responsive IL-12-conditioned iTregs induced only mild CNS inflammation and only when given in high numbers. Furthermore, iTregs retained an ability to suppress naive T cell clonal expansion in vivo and protected against the development of experimental autoimmune encephalomyelitis. Therefore, despite bearing predictive hallmarks of pathogenic effector function, previously Foxp3(+) iTregs have much lower proinflammatory potential than that of MBP-responsive Th1 cells. Our results demonstrate that autoprotective versus autoaggressive functions in iTregs are not simply a binary relationship to be determined by their relative expression of Foxp3 versus T-bet and IFN-gamma. |
