Neutralization of IL-4 reverses the nonresponsiveness of CD4+ T cells to regulatory T-cell induction in non-responder mouse strains.
It is well established that naive cells can be converted by TGF-β into CD4(+)CD25(+) regulatory T (Treg) cells with therapeutic potentials. Likewise, it is shown that all-trans retinoic acid (ATRA) can greatly enhance TGF-β-induced Treg conversion, a phenomenon which has mainly been studied in C57BL/6 mice. Here we show that, although purified naive cells are highly susceptible to Treg generation, total CD4(+) T-cell populations from different mouse strains display significantly different sensitivities to TGF-β/ATRA-induced Treg conversion. The resistance of "non-responder" strains is associated with an enhanced production of IL-4 by memory T cells as well as an increased sensitivity of naive T cells to the action of IL-4. Importantly, neutralization of IL-4 overcomes the differences, thereby enabling TGF-β/ATRA to generate large numbers of functional Treg cells from total CD4(+) T cells in a consistent manner across different mouse strains. Likewise, blockade of IL-4 significantly enhances TGF-β/ATRA-induced Treg conversion from human naive T cells in the presence of memory cells. These results show that the inherent resistance of "non-responder" mouse strains to Treg conversion induced by TGF-β and ATRA can be reverted by neutralization of IL-4 and that inhibiting the action of IL-4 is beneficial or even necessary for consistent inducible Treg generation.
Wang
Jun
J
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. J.Wang@lumc.nl
Han
Wanda G H
WG
Foks
Amanda C
AC
Huizinga
Tom W J
TW
Toes
Rene E M
RE
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
D007155:Immunologic Factors; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D014212:Tretinoin