CD8⁺ T regulatory cells in lupus

Abstract

T regulatory cells (Tregs) have a key role in the maintenance of immune homeostasis and the regulation of immune tolerance by preventing the inflammation and suppressing the autoimmune responses. Numerical and functional deficits of these cells have been reported in systemic lupus erythematosus (SLE) patients and mouse models of SLE, where their imbalance and dysregulated activities have been reported to significantly influence the disease pathogenesis, progression and outcomes. Most studies in SLE have focused on CD4+ Tregs and it has become clear that a critical role in the control of immune tolerance after the breakdown of self-tolerance is provided by CD8+ Tregs. Here we review the role, cellular and molecular phenotypes, and mechanisms of action of CD8+ Tregs in SLE, including ways to induce these cells for immunotherapeutic modulation in SLE.

Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus

“…Numerical and functional deficits of abnormalities in Treg subtypes have been reported to have a significant impact on the pathogenesis and outcome from patients with autoimmune disorders ( 22 – 26 ). Elucidation of the roles of various subsets of Treg ( Table 1 ) dedicated to immune balance will provide a novel therapeutic approach that governs immune tolerance for SLE remission ( 27 , 28 ). However, no definitive phenotypic markers or functions have been recognized to distinguish between these Treg subtype populations in SLE.…”

“…Cytotoxic Tregs are heterogeneous in periphery circulation and retain the ability to destroy T cell activation and proliferation to ensure immune homeostasis ( 71 ). CD8+ FoxP3+ Treg cells were first recognized in human tonsils, and CD8+ Treg cell subsets based on CD25+ expression may share similar suppressive capacity typically associated with CD4+ Treg ( 28 , 71 , 72 ). Isolated human CD8+ Tregs frequently express several cell surface molecules that include CD8, CD103, CD25, CD39, CD28, ICOS, CD122, CD39, CTLA-4, CXCR3, 4-1BB and lymphocyte activation gene 3 (LAG-3) ( 73 ).…”

“…Isolated human CD8+ Tregs frequently express several cell surface molecules that include CD8, CD103, CD25, CD39, CD28, ICOS, CD122, CD39, CTLA-4, CXCR3, 4-1BB and lymphocyte activation gene 3 (LAG-3) ( 73 ). Suppressive CD8+FoxP3+ Treg cells could decrease the proliferation of CD4+ effector T cells through the above mechanism, including cell-cell contact lysis through the granzyme/perforin, Fas/FasL signaling pathways and secreting inhibitory cytokines, and deprivation effector T cell growth by metabolic competition of IL-2 ( 28 , 71 , 74 – 76 ) ( Table 1B ).…”

“…Defective CD8+ Treg cells and function were found in murine lupus nephritis models ( 28 ), and adaptive transfer of suppressive CD8+CD103+CD39+ Tregs could inhibit chronic graft versus host disease in murine lupus nephritis model ( 43 ). Transfection plasmid DNA vectors encoding epitopes activated CD8+ cytotoxic T lymphocytes (CTL) to kill autoantibody-producing B cells and ameliorated the severity of lupus ( 44 ).…”

CD4+ and CD8+ regulatory T cell characterization in the rat using a unique transgenic Foxp3-EGFP model

“…The FOXP3 transcription factor is essential for the function of canonical natural CD4 + Treg [1]. CD8 + Treg is and heterogeneous cell population [9,10], as CD4 + Treg, but the phenotype and function of natural CD8 + FOXP3 + Treg is less well defined than for CD4 + FOXP3 + Treg [4]. CD8+ Foxp3+ Treg cells have been previously identified in human tonsils [11] and in blood of HIV-infected patients [12].…”