HSP70 Is a Major Contributor to the MHCII Ligandome and Inducer of Regulatory T Cells

Experimental models of autoimmunity have revealed anti-inflammatory effects of immunization with HSP70 or its derivative peptides. In depth cellular analysis of the effects of HSP70 immunization has shown the capacity of HSP70 to induce and expand self-tolerance promoting regulatory T cells (Tregs). In other words, in the models tolerance was re-established by the action of HSP70 specific Tregs. For the inflammation suppressive activity of antigen specific Tregs it is essential that the targeted antigen is ubiquitously expressed in the tissues. HSP70 family members, especially those that are stress-inducible, are widely expressed by stressed cells in the inflamed tissue due to the local presence of inflammatory mediators. In addition, cell stress is known to lead to autophagy, which in the case of chaperone mediated autophagy does lead to the preferential loading of HSP70 in MHC class II molecules. MHCII peptide elution profiles obtained from cells in a steady state have also revealed the dominating presence of HSP70 derived peptides in MHC class II molecules. For these reasons HSP70 is one of the most frequent cytosolic/nuclear MHCII natural ligand sources. HSP70, when presented by tolerizing antigen presenting cells in tissues, does induce Tregs, which seem to contribute to the tolerance promoting default setting of the healthy immune system.