Transient regulatory T-cells: a state attained by all activated human T-cells.
CD4(+)CD25(+)FOXP3(+) regulatory T-cells (T(regs)) form an important arm of the immune system responsible for suppressing untoward immune responses. T(regs) can be thymically derived or peripherally induced, even from CD4(+)CD25(-)FOXP3(-) T-cells. FOXP3 expression and in vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Here we show that virtually all human CD4(+)CD25(-)FOXP3(-) T-cells and CD8(+)CD25(-)FOXP3(-) T-cells attain a transient FOXP3(+)CD25(+) state during activation. In this state of activation, these cells possess the classic phenotype of T(regs), in that they express similar markers and inhibit in vitro proliferation of autologous CD4(+)CD25(-) T-cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. Our results show that, in humans, FOXP3 expression and T(reg) functionality are not exclusive features of a stable or unique lineage of T-cells but may also be a transient state attained by almost all T-cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce "T(regs)" may paradoxically result in induction of effector T-cells, unless stability is confirmed.
Pillai
Vinodh
V
Department of Pathology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
Ortega
Sterling B
SB
Wang
C K
CK
Karandikar
Nitin J
NJ
D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors