286 stress proteins, was seen to have no effect on bone marrow- derived dendritic cells, but at a higher dose led to an increased IL-10/INF-γ ratio in T cells. This skewing also indicated the induction of a regulatory mode in T cells and was shown to induce a state of T cell hyporesponsiveness and delay the rejection of cardiac allografts in rats (Mirza et al. 2006; Slack et al. 2007). More recently, we have shown that endogenous upregu- lation of HSP by HSP co-inducing compounds may also lead to the induction of HSP-specific Treg cells. In the mouse model of proteoglycan-induced arthritis, we have shown that oral administration of oregano-derived carvacrol led to the upregulation of HSP70 in gut Peyer’s patches and draining lymph nodes and to the suppression of disease development. Also, T cells were found to exhibit elevated HSP70-specific recall responses. Moreover, the T cells responding to oral carvacrol treatment were shown to be CD4+CD25+Foxp3+ in the spleen and in the joint, indicating that the disease suppression was mediated by the induction of genuine Treg cells (Wieten et al. 2010). A similar effect may have occurred in the case of triptolide- induced HSP70 expression, which may have yielded the protective effect in EAE models for multiple sclerosis (van Eden 2009). Genetic evidence for a disease suppressive role of endogenous HSP70 was obtained in a transgenic mouse model of dextran sulfate sodium-induced colitis. Reduced disease and less pro-inflammatory cytokine production were seen in HSP70-overexpressing animals. In HSF-1 mice, the opposite phenotype was observed, as disease worsened and more pro-inflammatory cytokines were produced (Tanaka et al. 2007). A similar study showed the disease suppressive role of HSP70 in bleomycin- induced pulmonary fibrosis (Tanaka et al. 2010). Recently, Shields et al. introduced the idea of certain HSP molecules acting as “resolution-associated molecular patterns” or RAMPs. RAMPs were proposed to exert immunological activity by restoring immune homeostasis by deactivating cells of the innate immune system and by expanding regulatory cells (Shields et al. 2011). While they accept the idea that most HSP will act as DAMPs, they propose some HSP molecules (HSP10, HSP27, alpha B- crystallin, and BiP or GRP78) to be exceptional and to act as RAMPs. In our opinion, the examples they cite have effects similar to those seen for members of major HSP families such as HSP60 and HSP70. HSP10 was formerly known as the early pregnancy factor and had an immune regulatory role in preventing of rejection of the allogeneic embryo. Since then, HSP10 was found to have immune regulatory effects in various other systems: serum levels were found to correlate with T cell receptor down-modulation (CD3ζ expression), proliferation of Jurkat T cell lines was inhibited, and in vitro, HSP10 pretreatment inhibited LPS- W. van Eden et al. stimulated TNF-α and IL-6 secretion by human peripheral blood mononuclear cells (Johnson et al. 2005). Recombinant HSP27 has a tendency to induce IL-10 secretion in cultured human monocytes, and it blocks differentiation of monocytes to dendritic cells (De et al. 2000; Laudanski et al. 2007). In monocytes, the HSP70 family member BiP was found to downregulate MHC and the co-stimulatory molecule CD86. Instead, it stimulated production of anti-inflammatory cytokines IL-1 receptor antagonist, soluble TNF receptor II, and IL-10 (Corrigall et al. 2004). Additional immunosuppressive effects of HSP have also been seen in the case of exosome-associated HSP70. Membrane-associated HSP72 obtained from tumor-derived exosomes were observed to mediate a suppressive activity in myeloid-derived suppressor cells. Possibly, this is one mechanism by which tumor immune surveillance is restrained (Chalmin et al. 2010). The possible further complexity of HSP-associated cellular export vesicles and cellular communications under stress conditions and its potential implications have already been discussed in an authoritative manner by de Maio in an earlier perspective and reflection article (De Maio 2011). HSP and immune homeostasis If we refute the possibility that HSP are DAMPs, and we recognize the prominent role of HSP in cognate interactions with the immune system, we are confronted with the question of what the actual immunological significance of HSP may be. The elevated levels of HSP in inflamed, traumatized, or reperfused tissues in combination with the extensive immune repertoire of cells with the capacity to recognize HSP indicate that these proteins may be biomarkers of damage, providing targets for immune mechanisms involved in restoration of tissue and immune homeostasis. With the recent rediscovery of regulatory T cells (Treg), the role of the immune system in homeostasis has received renewed interest. Also the reinterpretation of self/nonself discrimination, as was revamped by the “danger” concept, seems to have boosted our appreciation of mechanisms of immune homeostasis. Currently, there is a flurry of interest in the host–microbe interrelationships at the level of the gut microbiota. The immune system cannot tolerate becoming rampantly stim- ulated by foreign molecules, but has to figure out whether a certain stimulus is just microbial nonself or a signal of imminent danger. In the case of benign microbial nonself as present in our enteric microbiota, a carefully regulated response suffices or is even imperative. It is in this relationship that a major role for Treg cells is proposed. Despite many technical obstacles, it is now widely accepted