A case of mistaken identity: HSPs are no DAMPs but DAMPERs that Treg cells do exist and can suppress immune responses in an antigen-specific manner, also in areas other than the gut. There are two functional categories of Treg cells. Natural Treg cells are represented by a specialized subset of CD4+DC25+Foxp3+ T cells that are selected in the thymus on the basis of relatively high affinity self-recognition. The second group is inducible Treg cells. These CD4+ T cells, which are also mostly CD25+Foxp3+, are programmed in the peripheral lymphoid organs or in the tissues to adopt a regulatory status. Notably, HSPs are abundantly expressed in the thymus in the areas where positive selection of T cells takes place (Anderson et al. 2002). Therefore, HSP- specific natural Treg cells may be selected in the thymus, whereas HSP-specific induced Treg cells may originate from elevated HSP expression in stressed peripheral tissues. Besides their prominent role in the maintenance of immune homeostasis in relation to symbiotic interactions with the gut microbiota, Treg cells are implicated in the anti-inflammatory responses that are seen in autoimmunity, cancer, and infection (Vignali et al. 2008). During infection, Treg cells help to resolve the pro-inflammatory response, thereby reducing bystander damage. In addition, Treg cells may be even more fundamental in the organization of the immune response. For example, it has been shown that Treg cells may function to aid in efficient cell entry into sites of infection (Lund et al. 2008). On the basis of the findings in experimental animal models, new evidence seems to have surfaced that HSP can be antigens that stimulate the activity of Treg cells (see also previous section). For several reasons, this latter possibility may be plausible and attractive. Every cell in the body harbors the full spectrum of HSP molecules. Under stress, many of them are upregulated, and their fragments are processed and presented by MHC molecules on the cell surface. HSP70 may have a preferential position here. Some HSP70 family members (Hsc70 or HSPA8 and in addition DNAJB1 and HSPC) are involved in chaperone-mediated autophagy, a process whereby during stress or nutrient deprivation cytosolic proteins are reused by cells and are routed through a subcellular compartment that intersects with the MHC class II route (Majeski and Fred Dice 2004). This means that, especially under stress, fragments of HSP70 may be loaded into MHC class II products. Herewith HSP70 epitopes are being presented in a preferential manner to CD4+ T cells, which includes Tregs. Based on other arguments, such as the autophagy-mediated disposition of proteins with a long half-life and MHC binding predictions, HSP70 has already been proposed as an important source of peptides to be loaded onto MHC class II molecules, also in the absence of stress (Paludan et al. 2005). A mass spectroscopy analysis of peptides eluted from MHC class II obtained from stressed human B cells, revealed that HSP70 (HSPA1A, 287 HSPA6, and HSPA8) fragments composed a major portion of the bound collection of peptides (Dengjel et al. 2005). Thus, the immune system, including Treg cells, has ample opportunity to encounter MHC-presented HSP epitopes, and this will be especially prevalent during inflammation or other stress conditions. For Treg cell-mediated immune homeostasis this situa- tion may be ideal. When trying to imagine how antigen- specific Treg cells could work, one has to realize that it is unlikely that effective regulation is secondary to the presence of a very small number of autoantigen-specific Treg cells present in a polyclonal population. As already pointed out by Shevach, a more likely scenario is that polyclonal Treg cells are able to exert control because they are being regularly activated through their TCR by complexes of MHC class II and ubiquitous self-peptides (Shevach 2009). If so, HSPs would provide an excellent collection of prominently expressed—certainly under stress— ubiquitous self antigens. This qualifies them very well as targets for T cell regulation. HSPs are further implicated in many situations where host immune homeostasis is challenged. Figure 1 represents three typical scenarios: sterile tissue damage (autoimmune inflam- mation, reperfusion injury, heat stress), true danger imposed by pathogen invasion (infection), and commensalism/symbiosis (e.g., exposure to gut microbiota). Maintenance of tissue homeostasis is required in all these instances, and one may assume that the immune system is having a major role here. This may well include the responses of the immune system to HSP. Given the postulated capacity of HSPs to trigger Treg cells, it seems attractive to attribute, at least in part, the restoration of tissue and immune homeostasis to the activity of HSP-specific Treg cells. Extracellular versus intracellular HSP There exist two ways by which heat shock proteins can interact with the immune system (Fig. 2). First of all, their intracellular upregulation as a consequence of cell stress will lead to upregulated MHC presentation of HSP frag- ments (peptides) at the cell surface making them visible to T cells. Secondly, they may be translocated by yet undefined mechanisms, as complete molecules to the cell surface or to the extracellular environment. This would allow them to be encountered by NK cells, antibodies, and antigen-presenting cells. Besides active translocation, cell necrosis is probably a mechanism through which HSPs are released into the extracellular environment. It is safe to conclude that these two distinct contexts for HSP interactions with the immune system will lead to distinct immunological outcomes. In principle, DAMP producing cell death is proposed to result mainly from necrosis. Whether cell death is immu-