In sum, modulation of the balance between autoimmunity and immunoregulation, and thus subsequent induction or prevention of T1D, might rely on the dual function of the innate immune players involved in the disease. Depending on timing and whether β-cell antigens are present, TLR-mediated effects will differentially affect the FK506 cost development of autoimmunity. The opposing roles of infections in T1D, which also depend on timing and vary in terms of damage to β cells 2, may thus be accounted for by the capacity of viruses to differentially affect such innate immune factors depending on the context. For instance, TLR2 signaling, and subsequent activation of
APCs/T cells and production of inflammatory cytokines, may promote autoimmune processes when β-cell antigens are present, but also appear to counter autoimmunity by enhancing and invigorating CD4+CD25+ Tregs and conferring
DCs with tolerogenic properties. Previous work has shown that TLR2 signaling enhances the function of CD4+CD25+ Tregs 22 and regulates their expansion and activity 29, 30. TLR2 was proposed to control antimicrobial immunity by transiently limiting the function of natural Tregs (thus permitting T-cell immunity) while enhancing their number (thus participating in terminating it). Accordingly, we found that acute anti-LCMV immunity coincided HDAC inhibitor with ineffective activity of CD4+CD25+ Tregs (data not shown) but resulted in their increased frequency and function. TLR2 might thus act to regulate antiviral immunity, by enhancing the number and function of Tregs to control it,
but impairing these cells as long as the invading virus is present. Intriguingly, to date, there is no evidence that LCMV particles can bind to TLR2. But while TLR2 is responsible for sensing components from micro-organisms, it can also recognize molecular motifs from certain endogenous ligands. In this regard, the chaperone HSP60 was shown to enhance the function of CD4+CD25+ Tregs through TLR2 signaling 22. It is thus possible that viral infection triggers the release of molecules such as HSPs, which promote the direct enhancement of CD4+CD25+ Non-specific serine/threonine protein kinase Tregs via TLR2. This might constitute a means to recognize and control potentially harmful immune processes through innate immunity. Such absence of antigenic specificity could enable control of immunity to infection not only by viruses but also bacteria or other pathogens. In particular, in the hygiene hypothesis it is proposed that a number of different infections in early life contribute to reduced susceptibility to T1D 46. The capacity of the immune system to control immunopathology independent of antigen may thus account for the ability of numerous infections or non-infectious pro-inflammatory agents to protect from T1D in experimental models for this disease 13.
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