Toll reg.

IMMUNOLOGY

REVIEW ARTICLE

Toll-like receptors and immune regulation: their direct and indirect modulation on regulatory CD4+ CD25+ T cells

Guangwei Liu and Yong Zhao*
Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

Summary Regulatory CD4+ CD25+ T (Treg) cellswith the ability to suppress host immune responses against self- or non-self antigens play important roles in the processes of autoimmunity, transplant rejection, infectious diseases and cancers. The proper regulation of CD4+ CD25+ Treg cells is thus critical for optimal immune responses. Toll-like receptor (TLR)-mediated recognition of specific structures of invading pathogens initiates innate aswell as adaptive immune responses via antigen-presenting cells (APCs). Interestingly, new evidence suggests that TLR signalling may directly or indirectly regulate the immunosuppressive function of CD4+ CD25+ Treg cells in immune responses. TLR signalling may shift the balance between CD4+ T-helper cells and Treg cells, and subsequently influence the outcome of the immune response. Thisimmunomodulation pathway may therefore have potential applications in the treatment of graft rejection, autoimmune diseases, infection diseases and cancers. Keywords: Toll-like receptors; regulatory CD4+ CD25+ T cells; immune response; immune tolerance; autoimmune disease

doi:10.1111/j.1365-2567.2007.02651.x Received 26 November 2006; revised 18 March 2007; accepted 3 May 2007. Correspondence: Dr YongZhao, Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Beijing, China 100101. Email: zhaoy@ioz.ac.cn Senior author: Yong Zhao

Introduction
The family of Toll-like receptors (TLRs) is a major class of receptors that recognize molecular patterns associated with pathogensincluding bacteria, viruses, fungi and protozoa. It was commonly accepted that TLR-mediated recognition of specific structures of invading pathogens initiates innate as well as adaptive immune responses via dendritic cells (DCs) or other antigen-presenting cells (APCs).1–3 However, there is emerging evidence that TLR signalling participates in inflammation and immune responses that are driven by self-,allo- or xenoantigens.4–7 TLR signalling has been demonstrated to be involved in the immune recognition of allo- or xenografts and the occurrence of autoimmunity both in experimental and in clinical studies.5,8–10 This observation was strongly supported by the expression of TLRs on almost

all immune cells and the endogenous expression of their ligands on mammalian cells. However, there hasrecently been an explosion of renewed interest in regulatory T (Treg) cells, especially on three postulated CD4+ Treg cell populations: the naturally occurring and inducing CD4+ CD25+ Treg cells, and two inducible populations, type 1 regulatory T (Tr1) cells and type 3 regulatory T (Th3) cells.11–13 It is clear now that the CD4+ CD25+ Treg cell population not only critically contributes to themaintenance of self-tolerance but also has the potential to prevent the immune rejection of allografts.14,15 Recent studies have shown that TLR signalling may directly or indirectly regulate the immunosuppressive function of CD4+ CD25+ Treg cells in graft rejection, autoimmune diseases, infectious diseases and cancers,16–19 which is the focus of the present review.

Abbreviations: APC,antigen-presenting cell; DC, dendritic cell; DD, death domain; Foxp3, Forkhead box protein 3; IFN, interferon; IRAK, IL-1R-associated kinase; IRF-3, interferon regulatory factor 3; IL, interleukin; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MyD88, myeloid differentiation primary response protein 88; Mal, MyD88-adaptor-like; NF-jB, nuclear factor jB; PAMP, pathogen-associated molecular pattern; TGF,...