Aling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation on the transcription issue Foxo1, which benefits in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function through controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.CORRESPONDENCE Peter S. Heeger: [email protected] Abbreviations employed: DAF, decayaccelerating factor; nT reg cell, natural thymus derived T reg cell; T conv cell, traditional T cell.CD4+CD25+ regulatory T cells (T reg cells) expressing the forkhead box transcription fac tor Foxp3 are needed for immune homeo stasis and selftolerance (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003). Mice get Euphorbia factor L3 deficient in Foxp3 exhibit systemic autoimmu nity, and CD4+CD25+ T cells obtained from these animals are unable to mediate suppression (Fontenot et al., 2003, 2005; Hori et al., 2003; Khattri et al., 2003). Reconstituting Foxp3 expression rescues suppressive capacity, and adoptive transfer of Foxp3+CD4+ T cells into Foxp3deficient animals rescues selftolerance (Fontenot et al., 2003, 2005; Hori et al., 2003; Khattri et al., 2003). CD4+Foxp3+ T reg cells that mature within the thymus, referred to as thymic or organic T reg cells (nT reg cells), are particu larly significant for preventing autoimmunity, though a recent publication supports the con clusion that naive T cells induced to expressW.h. Kwan and W. van der Touw contributed equally to this paper.Foxp3 inside the periphery (induced T reg cells or iT reg cells) are especially required for principal taining tolerance at mucosal surfaces, which includes the gut and the lungs (Josefowicz et al., 2012). CD4+Foxp3+ nT reg cells and iT reg cells have each been shown to regulate pathogenic allo reactive T cells induced to a transplanted organ (Ochando et al., 2006; Nagahama et al., 2007; Joffre et al., 2008; Zhang et al., 2009; Fan et al., 2010; Nadig et al., 2010; Kendal et al., 2011). Irrespective of their origin, the requisite func tion of T reg cells in preventing autoimmunity should be stringently controlled so as to permit induction, expansion, and function of protective immune responses. Identified molecular signals which can inhibit T reg cell function in response to infection incorporate IL6, IL1, and multiple2013 Kwan et al. This short article is distributed under the terms of an AttributionNoncommercial hare Alike o Mirror Websites license for the first six months soon after the publication date (see http://www.rupress.org/terms). Immediately after six months it can be readily available beneath a Creative Commons License (Attribution oncommercial hare Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/ by-nc-sa/3.0/).The Rockefeller University Press 30.00 J. Exp. Med. 2013 Vol. 210 No. two PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19960242 257-268 www.jem.org/cgi/doi/10.1084/jem.TLR ligands (Pasare and Medzhitov, 2003; O’Sullivan et al., 2006; Torchinsky et al., 2009; Hu et al., 2011). Signals trans mitted by these molecules to T reg cells inhibit or limit Foxp3 expression, preferentially yielding Th1 and/or Th17 effector cells which facilitate expansion of pathogenreactive T cell responses (Yang et al., 2008). Broad.