Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.
Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD4(+)CD25(+) T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines. We found that all dividing Teff cells expressed FOXP3, but only transiently, and at levels that were significantly lower than those in suppressive nTregs. This temporary expression in Teff cells was insufficient to suppress expression of reported targets of FOXP3 repressor activity, including CD127, IL-2 and IFN-gamma, and was not correlated with induction of a nTreg phenotype. Thus expression of FOXP3 is a normal consequence of CD4(+) T cell activation and, in humans, it can no longer be used as an exclusive marker of nTregs. These data indicate that our current understanding of how FOXP3 contributes to immune tolerance in humans needs to be re-evaluated.
Allan
Sarah E
SE
Department of Surgery, University of British Columbia, and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, 2660 Oak Street, Vancouver, Canada.
Crome
Sarah Q
SQ
Crellin
Natasha K
NK
Passerini
Laura
L
Steiner
Theodore S
TS
Bacchetta
Rosa
R
Roncarolo
Maria G
MG
Levings
Megan K
MK
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002460:Cell Line; D049109:Cell Proliferation; D017635:Clonal Anergy; D018920:Coculture Techniques; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D005408:Flagellin / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type; D008074:Lipoproteins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology; D000099192:CD69 Antigens
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D003545:Cysteine; D016207:Cytokines; D005408:Flagellin; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007371:Interferon-gamma; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D037181:Lectins, C-Type; D008074:Lipoproteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D051193:Toll-Like Receptors; D000099192:CD69 Antigens; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C418974:FOXP3 protein, human; C491405:TNFRSF18 protein, human; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine