TNF downmodulates the function of human CD4+CD25hi T-regulatory cells.
CD4+CD25+ T-regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. However, little is known about the exogenous factors that regulate their differentiation and function. Here, we report that TNF inhibits the suppressive function of both naturally occurring CD4+CD25+ Tregs and TGFbeta1-induced CD4+CD25+ T-regulatory cells. The mechanism of this inhibition involves signaling through TNFRII that is constitutively expressed selectively on unstimulated Tregs and that is up-regulated by TNF. TNF-mediated inhibition of suppressive function is related to a decrease in FoxP3 mRNA and protein expression by the Tregs. Notably, CD4+CD25hi Tregs isolated from patients with active rheumatoid arthritis (RA) expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. Treatment with anti-TNF antibody (infliximab) increased FOXP3 mRNA and protein expression by CD4+CD25hi Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4+CD25+ Treg activity.
Autoimmunity Branch, the Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institute of Health (NIAMS/NIH), Bethesda, MD 20892, USA. xvalencia@mail.nih.gov
Xavier
X
Valencia
Geoffrey
G
Stephens
Raphaela
R
Goldbach-Mansky
Mildred
M
Wilson
Ethan M
EM
Shevach
Peter E
PE
Lipsky
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D000069285:Infliximab; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab