Figure 2

HSP60 uses both innate and adaptive immune pathways to enhance regulatory T cell (Treg) function. (a) HSP60 and HSP60-derived epitopes are able to bind to Toll-like receptors (TLRs). By binding to TLRs present on dendritic cells (DCs), HSP60 can induce maturation of DCs or cytokine production by them [9, 11], which could possibly cause induction of Tregs. Both DCs and Tregs are able to produce IL-10, which inhibits activation of effector T cells. To suppress the ongoing immune response, HSP60-induced Tregs could inhibit activation of effector T cells (Teffs) by cell-cell contact and/or production of IL-10, or other cytokines, such as transforming growth factor β [14]. (b) Pan-HLA-DR (pan-DR) binding HSP60 epitopes are either presented to the Tregs in a major histocompatibility complex (MHC) II molecule by DCs, which could stimulate Tregs, or they are able to bind to TLRs on the Tregs [28] and thereby enhance Treg function. We hypothesize that HSP60 and HSP60-derived epitopes can enhance or induce Tregs by signalling through both the T cell receptor (TCR) and TLRs at the same time. HSP60 epitopes may bind directly to TLRs on the T cells, or to TLRs on the DCs, which could indirectly enhance the immune response. (c) We hypothesize that a combination of a TCR signal by a HSP60 pan-DR binding epitope and a TLR signal by a pathogenic pattern could enhance the HSP60-induced tolerogenic response, causing a stronger and longer lasting immune regulatory effect.