Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators.
FTY720 has been used to control inflammatory lesions, but the mechanisms by which the drug acts in vivo are poorly understood. Such mechanisms may result primarily from effects on lymphocyte and dendritic cell homing to lymphoid and inflammatory sites. We demonstrate that FTY720 may also act by causing the conversion of TCR-stimulated nonregulatory CD4(+) T cells to Foxp3(+)CD4(+) regulatory T cells and by enhancing their suppressive activity. In a model in which mice were ocularly infected with HSV, daily treatment with FTY720 resulted in significantly diminished ocular lesions. The treated animals showed increased frequencies of Foxp3(+) T cells in lymphoid organs and at two inflammatory sites, namely cornea and trigeminal ganglia. In a second series of experiments, immunized DO11.10RAG2(-/-) animals, normally lacking endogenous Foxp3(+) T cells, that were given FTY720 treatment developed high frequencies of Foxp3(+) regulatory T cells in lymph nodes. Some converted cells persisted in treated animals for several weeks after drug administration was discontinued. Finally, FTY720 could effectively induce Foxp3-expressing cells from Foxp3(-) cells in vitro, an effect inhibited by anti-TGF-beta or the proinflammatory cytokine IL-6. Accordingly, the anti-inflammatory effects of FTY720 could be mediated at least in part by its ability to cause the conversion of Ag-stimulated conventional T cells to become Foxp3(+) regulators. The use of FTY720 along with Ag administration could represent a useful therapeutic means to selectively expand Ag-specific regulators, which could be valuable in many clinical situations such as allotransplants, some autoimmunities, as well as with some chronic infections.
Sehrawat
Sharvan
S
Comparative and Experimental Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996-0845, USA.
Rouse
Barry T
BT
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016849:Keratitis, Herpetic / Q000188:drug therapy / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008817:Mice, Mutant Strains; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016212:Transforming Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine