Peripheral Anergy

The mechanisms responsible for peripheral tolerance are usually classified into those acting directly on the responding T cell (intrinsic tolerance) and those mediated by additional subsets of immune cells (extrinsic tolerance), including DC and regulatory T cells.38

Anergy, a main feature of tolerance, can be defined as a long-lasting inability of antigen-specific T cells to proliferate upon rechallenge with fully competent antigen presenting cells (APC). Classically, anergy is induced when a T cell meets its antigen in the absence of costimulation, and the resulting state of nonresponsiveness can be fully reversed by the addition of exogenous IL-2.39 Alternatively, T cell anergy can be induced when CD4+ or CD8+ T cells are activated in

Figure 1. The molecular basis ofT cell suppression by IL-10. Stimulation of CD28 by CD80/86 surface costimulatory molecules expressed by antigen presenting cells (APC) leads to tyrosine phosphorylation of CD28. Ligation of IL-10 receptor (IL-1 OR) at the time of CD28 stimulation inhibits tyrosine phosphorylation of CD28. As a consecutive event for signal transduction, phosphatidyl-inositol 3-kinase (PI3-K) binds to CD28 by itsp85 subunit. IL-10 exerts its biological functions through the activation of Jakl andTyk2, the members of the receptor-associated Janus tyrosine kinases family and STAT1 and STAT3. The engagement oflL-lORby IL-10 inhibits CD28 both tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-K) binding. Similarly, CTLA-4, a negative regulator of T cell function, associates with the TCR complex t, chain in T cells and utilizes the tyrosine phosphatase SHP-2 to dephosphorylate CD3^ chain.

Figure 1. The molecular basis ofT cell suppression by IL-10. Stimulation of CD28 by CD80/86 surface costimulatory molecules expressed by antigen presenting cells (APC) leads to tyrosine phosphorylation of CD28. Ligation of IL-10 receptor (IL-1 OR) at the time of CD28 stimulation inhibits tyrosine phosphorylation of CD28. As a consecutive event for signal transduction, phosphatidyl-inositol 3-kinase (PI3-K) binds to CD28 by itsp85 subunit. IL-10 exerts its biological functions through the activation of Jakl andTyk2, the members of the receptor-associated Janus tyrosine kinases family and STAT1 and STAT3. The engagement oflL-lORby IL-10 inhibits CD28 both tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-K) binding. Similarly, CTLA-4, a negative regulator of T cell function, associates with the TCR complex t, chain in T cells and utilizes the tyrosine phosphatase SHP-2 to dephosphorylate CD3^ chain.

the presence of IL-10 or with APC that have been previously treated with IL-10.22,40 This effect of IL-10 is partly due to the ability of IL-10 to downregulate costimulatory molecules on APC (see below), but also involves direct effects on the T cells themselves. As a matter of fact, purified T cells activated with anti-CD3 mAb in the presence of IL-10 also become nonresponsive.22 Interestingly, the anergic state of IL-10-treated T cells cannot be reversed by the addition of exogenous IL-2 (or IL-15), indicating that IL-10-anergized cells are not equivalent to those induced by costimulation blockade.22 However, reversibility of IL-10 immunosuppressive properties by other cytokines remains debated. In an in vitro model of allergen-specific immunotherapy, CD4+ T cell proliferation and cytokine production initially inhibited by IL-10 is fully recovered after the administration of IL-2,36 which underlines the importance of tissue microenvironment cytokine balance in determining the ultimate outcome of an immune response.

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