CD8+ Tregs in lupus, autoimmunity, and beyond

Abstract

While CD4(+)CD25(high) regulatory T cells (Tregs) have garnered much attention for their role in the maintenance of immune homeostasis, recent findings have shown that subsets of CD8(+) T cells (CD8(+) Tregs) display immunoregulatory functions as well. Both CD4(+) Tregs and CD8(+) Tregs appear impaired in number and/or function in several autoimmune diseases and in experimental animal models of autoimmunity, suggesting the possibility of immunotherapeutic targeting of these cells for improved management of autoimmune conditions. Our group has developed a strategy to induce CD8(+) Tregs in autoimmune mice through the use of a tolerogenic self-peptide, and new information has been gained on the phenotype, function and role of induced CD8(+) Tregs in autoimmunity. Here we present an overview of the role and mechanisms of action of CD8(+) Tregs in autoimmunity, with a special focus on lupus. We also discuss the potential role of CD8(+) Tregs in other diseases, including chronic infection and cancer.

Figure 1. Mechanisms of Suppression of CD8⁺ Tregs

A) CD8⁺ Tregs secrete cytokines/chemokines such as IFNγ, TGFβ, IL-16, IL-10, and CCL4 that suppress immune responses. B) CD8⁺ Tregs render APCs tolerogenic by downregulating stimulatory molecules, such as CD80 and CD86, and upregulating inhibitory receptors, such as ILT3 and ILT4. C) CD8⁺ Tregs can suppress in a contact-dependent fashion that may be dependent on surface expression of molecules such as membrane-bound TGFβ or CTLA-4. D) MHC Class I restricted CD8⁺ Tregs are capable to kill activated CD4⁺ T effectors that express Qa-1/HLA-E.