CD8 regulates T regulatory cell production of IL-6 and maintains their suppressive phenotype in allergic lung disease.
Naturally occurring CD4(+)CD25(+)Foxp3(+) T regulatory cells (nTregs) regulate lung allergic responses through production of IL-10 and TGF-β. nTregs from CD8(-/-) mice failed to suppress lung allergic responses and were characterized by reduced levels of Foxp3, IL-10, and TGF-β, and high levels of IL-6. Administration of anti-IL-6 or anti-IL-6R to wild-type recipients prior to transfer of CD8(-/-) nTregs restored suppression. nTregs from IL-6(-/-) mice were suppressive, but lost this capability if incubated with IL-6 prior to transfer. The importance of CD8 in regulating the production of IL-6 in nTregs was demonstrated by the loss of suppression and increases in IL-6 following transfer of nTregs from wild-type donors depleted of CD8(+) cells. Transfer of nTregs from CD8(-/-) donors reconstituted with CD8(+) T cells was suppressive, and accordingly, IL-6 levels were reduced. These data identify the critical role of CD8-T regulatory cell interactions in regulating the suppressive phenotype of nTregs through control of IL-6 production.
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
Anthony
A
Joetham
Masakazu
M
Okamoto
Katsuyuki
K
Takeda
Michaela
M
Schedel
Hiroshi
H
Ohnishi
Azzeddine
A
Dakhama
Erwin W
EW
Gelfand
D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta; D016753:Interleukin-10