While CD4+CD25high 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. been gained around 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 contamination and cancer. through CD40-activated B cells depends on IFNγ IL-2 IL-4 and CTLA-4; these Tregs are CD8high and express Foxp3 CD25 CD27 CD28 and CD62L [42]. One subset of CD8+ Tregs suppressed T effector cell function in healthy human subjects after injection of immature DC pulsed with influenza matrix peptide [43]. Recently in a model of Anterior Chamber-Associated Immune Deviation (ACAID) it has been found that ACAID-induced CD8+ Tregs secrete TGFβ and express CD94 and NKG2A [44]. While the role SB 743921 of IL-2 and TGFβ in the induction of CD4+CD25+ Tregs is usually well established [45] the methods of induction of CD8+ Tregs are as diverse as the subsets reported. Table 1 lists the CD8+ Tregs currently identified in the literature. Table 1 CD8+ Tregs Subtypes 3 Markers of CD8+ Tregs A specific marker for identification of CD8+ Tregs is still elusive. Many of the markers for subsets of CD8+ Tregs overlap with markers for CD4+ Tregs e.g. surface CD25 [25 30 38 39 46 and intracellular Foxp3 [27 30 37 39 46 While Foxp3 expression has been suggested as a unique marker for the identification of both CD4+ Tregs and CD8+ Tregs the finding that TCR activation also upregulates Foxp3 expression in cells without significant regulatory capacity [10 50 diminishes enthusiasm for this idea. It has been argued that non-regulatory Foxp3+ T cells could represent a dormant reservoir with the potential to become regulatory cells after homeostatic growth [53]. Additionally Foxp3 is usually expressed in human and murine non-lymphoid cells [54-56] and in humans non-regulatory cells can display transient upregulation of Foxp3+ [57 58 It has been Rabbit polyclonal to SP1. debated in the literature whether CD28 is present [47 48 or absent [33 35 59 on the surface of CD8+ Tregs. Data from our lab suggest that SB 743921 Foxp3 expression might represent a better indicator of a suppressive phenotype because both CD28- SB 743921 and CD28+ CD8+ Tregs that express Foxp3 can mediate suppression [47-49]. 4 Mechanisms of Suppression Not unlike their CD4+ Treg counterparts [63] CD8+ Tregs suppress through a variety of mechanisms that include secretion of cytokines cell-to-cell contact induction of a tolerogenic phenotype in APCs that can then induce regulatory CD4+ T cells and cytotoxic activity (Physique 1). In the case of suppression through cytokine secretion different subsets of CD8+ Tregs are reported to suppress through the secretion of different cytokines. Among the cytokines and chemokines reported to play a suppressive role are IL-10 [26 27 40 41 59 60 64 65 TGFβ [25 47 66 IFNγ [69] IL-16 [70] and CCL4 [39]. Some CD8+ Treg subsets in a manner similar to Tregs can suppress through a cell contact dependent mechanism [29 30 37 46 60 Additionally membrane bound TGFβ and CTLA-4 play a role in cell-cell contact dependent mechanisms of CD8+ Treg-mediated suppression [25 38 Physique 1 Mechanisms of Suppression of CD8+ Tregs CD8+CD28- Tregs can also render APCs tolerogenic through the upregulation of inhibitory receptors such as immunoglobulin-like transcript (ILT)-3 and ILT-4 on APCs [71 72 Tolerogenic APCs can then SB 743921 have an anti-inflammatory function and induce anergy and possible regulatory functions in CD4+ T cells [71 73 74 One study has shown a CD8+CD28–mediated downregulation of the costimulatory ligands CD80 and CD86 on APCs as important in the suppression of CD4+ T cell responses [75] and another study has reported that CD80 and CD86 play an important role in the suppressive activity of CD8+CD122+ T cells [76]. Finally another mechanism of suppression for CD8+ Tregs is usually cytolysis of antigen activated CD4+ Th cells which is dependent on the expression of the MHC class 1b molecule Qa-1 (HLA-E in humans) [77-80]. 5 CD8+ Tregs and Lupus 5. 1 Lupus-prone Murine Models We as well as others have.