Abstract
Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA) and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs) have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs). Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides) are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation.
Highlights
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
CD8+CD28−Foxp3+ Treg cells are probably the subset best characterized [9]. The activation of these cells is antigen specific [major histocompatibility complex (MHC)-I class-restricted], and their suppressor mechanism involves the induction of a tolerogenic phenotype in antigen-presenting cells (APCs) by the increased expression of immunoglobulin-like transcript 3 (ILT3) and ILT4
ILT3 and ILT4 suppress the activation of nuclear factorκB mediated by CD40, which in turn reduces the transcription of co-stimulatory molecules such as CD80 and CD86 [9,10,11]
Summary
CD4+CD25highFoxP3+ Tregs can prevent autoimmune diseases by maintaining the tolerance to self-antigens. ILT3 and ILT4 suppress the activation of nuclear factorκB mediated by CD40, which in turn reduces the transcription of co-stimulatory molecules such as CD80 and CD86 [9,10,11] These tolerogenic APCs in turn promote an anergic phenotype on naive CD4+ and CD8+ T cells, which could acquire similar regulatory functions spreading the induction of tolerance [10]. Activated T cells transiently increase the expression of CTLA4, which is important to limit the expansion of activated T cells during an immune response This cell surface molecule is expressed constitutively by Tregs endowing them with the potential to control T-cell activation through CD28 blockade (Figure 1). By inducing IL-2 deprivation and secreting perforins and granzymes, Tregs at the site of inflammation increase the susceptibility of Teff cells and other cells such as B cells and monocytes to cell death [23, 24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
