title: Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3.
abstract: The role of CTLA-4 in regulatory T cell (Treg) function is not well understood. We have examined the role of CTLA-4 and its relationship with the transcription factor FoxP3 using a model of Treg induction in human peripheral blood. Activation of human CD4(+)CD25(-) T cells resulted in the appearance of a de novo population of FoxP3-expressing cells within 48 h. These cells expressed high levels of CTLA-4 and cell sorting on expression of CTLA-4 strongly enriched for FoxP3(+)-expressing cells with suppressive function. Culture in IL-2 alone also generated cells with suppressive capacity that also correlated with the appearance of CTLA-4. To directly test the role of CTLA-4, we transfected resting human T cells with CTLA-4 and found that this method conferred suppression, similar to that of natural Tregs, even though these cells did not express FoxP3. Furthermore, transfection of FoxP3 did not induce CTLA-4 and these cells were not suppressive. By separating the expression of CTLA-4 and FoxP3, our data show that FoxP3 expression alone is insufficient to up-regulate CTLA-4; however, activation of CD4(+)CD25(-) T cells can induce both FoxP3 and CTLA-4 in a subpopulation of T cells that are capable of suppression. These data suggest that the acquisition of suppressive behavior by activated CD4(+)CD25(-) T cells requires the expression of CTLA-4, a feature that appears to be facilitated by, but is not dependent on, expression of FoxP3.
authors.affiliation: Division of Immunity and Infection, Medical Research Council Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Claire N
authors.initials: CN
authors.lastname: Manzotti
authors.forename: Fiona
authors.initials: F
authors.lastname: Burke
authors.forename: Laure
authors.initials: L
authors.lastname: Dussably
authors.forename: Omar
authors.initials: O
authors.lastname: Qureshi
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit