IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4+CD25+ regulatory T cell which jointly restrain CD4+CD25- cell activation.
The benefits of immunotherapy by regulatory T (Treg) cells are unpredictable partially due to the uncertainty of their suppressive mechanism. In fact, various suppressive mechanisms have been proposed but each remains controversial. To better understand Treg-mediated suppression, we have investigated factors which may influence the suppressive effects. In an in vitro suppression assay, over-expression of anti-apoptotic Bcl2 enhancing survival of conventional T responder cells (Tconvs) did not subvert Treg-mediated suppression. In contrast, enhancing activation of Tconvs by increasing the potency of calcium signals completely abrogated Treg-mediated suppression. While Tregs were incapable of suppressing already activated Tconvs, they prevented expression of activation markers on naïve Tconvs during activation, thereby indicating that Tregs mediate suppression through controlling early activation stage. Interestingly, IL-2 deprivation or TGF-beta, two suppressive mechanisms, did not effectively inhibit Tconv activation and proliferation when applied alone. In contrast, IL-2 deprivation combined with TGF-beta suppressed Tconv activation as potently as Tregs. More importantly, in the transwell system, that separates Tregs from Tconvs, TGF-beta contributed to Treg suppression under IL-2 depriving condition. In conclusion, these two suppressive mechanisms acting in concert may be necessary to effectively restrain the early activation of Tconvs.
Wang
Guohua
G
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
Khattar
Mithun
M
Guo
Zhiyong
Z
Miyahara
Yoshihiro
Y
Linkes
Sean P
SP
Sun
Zongquan
Z
He
Xiaoshun
X
Stepkowski
Stanislaw M
SM
Chen
Wenhao
W
D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D051927:CD24 Antigen; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta