Distinct regulatory roles of transforming growth factor-beta and interleukin-4 in the development and maintenance of natural and induced CD4+ CD25+ Foxp3+ regulatory T cells.
The development and function of CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) are strictly regulated by cytokines. Here we show that transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4) play a crucial and antagonistic role in the development of Tregs. Additionally, these cytokines also have distinct effects on the maintenance of natural (nTregs) and antigen-induced (iTregs) Tregs. Using double-staining and tracking of proliferation of purified and carboxyflourescein succinimidyl ester (CFSE)-labelled mouse T-cell subpopulations we demonstrated that CD4(+) CD25(+) Foxp3(+) iTregs develop upon alloantigenic stimulation in the presence of TGF-beta exclusively from CD4(+) CD25(-) Foxp3(-) precursors. Both the induction of Foxp3 expression and Treg proliferation were prevented when the cells were stimulated in the presence of IL-4. By contrast, nTregs did not proliferate in the presence of the antigen and TGF-beta, and partially lost their Foxp3 expression. IL-4 not only prevented the development of iTregs, but also down-regulated the level of Foxp3 mRNA and decreased the number of Foxp3(+) cells in a population of iTregs. Further analyses proved that IL-4 decreased the expression of Foxp3 only in a population of iTregs, whereas it substantially supported the survival of nTregs. Functional experiments showed that Tregs induced in the presence of alloantigen and TGF-beta inhibited, on a per-cell basis, cell proliferation comparably to nTregs, and their suppressive capacity was not modulated by IL-4. These data suggest that TGF-beta and IL-4 differentially regulate the development of Tregs and distinctly sustain Foxp3 expression and the number of nTregs and iTregs, but have no influence on the suppressive activity of Tregs on a per-cell basis.
Prochazkova
Jana
J
Institute of Molecular Genetics, Academy of Sciences, Videnska, Prague, Czech Republic.
Fric
Jan
J
Pokorna
Katerina
K
Neuwirth
Ales
A
Krulova
Magdalena
M
Zajicova
Alena
A
Holan
Vladimir
V
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4