Neutralization of IL-4 reverses the nonresponsiveness of CD4(+) T cells to regulatory T-cell induction in non-responder mouse strains

Abstract

It is well established that naive cells can be converted by TGF-beta into CD4(+)CD25(+) regulatory T (Treg) cells with therapeutic potentials Likewise it is shown that all-trans retinoic acid (ATRA) can greatly enhance TGF-beta-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-beta/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-beta/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-beta/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-beta 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 (C) 2010 Elsevier Ltd All rights reserved