CD8+ T regulatory cells in lupus

Abstract

T regulatory cells (T_regs) 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⁺ T_regs 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⁺ T_regs. Here we review the role, cellular and molecular phenotypes, and mechanisms of action of CD8⁺ T_regs in SLE, including ways to induce these cells for immunotherapeutic modulation in SLE.

Keywords: CD8+ Tregs; anti-DNA Ab; immune homeostasis; immune tolerance; lupus.

Figure 1

CD8⁺ T_regs SLE. In SLE, subsets of CD8⁺CD25⁺FoxP3⁺ T_regs—whose additional phenotypic markers are schematically depicted here—can suppress the activity of T effector (T_eff) cells and APCs, also suppressing autoantibody production through the secretion of TGF-β and other cytokines/chemokines. APC, antigen presenting cells; LAG-3, lymphocyte activation gene 3; SLE, systemic lupus erythematosus; T_regs, T regulatory cells; and Teff, T effector. Modified from Martha R. Vieyra-Lobato, Jorge Vela-Ojeda, Laura Montiel-Cervantes, Rubén López-Santiago, Martha C. Moreno-Lafont, “Description of CD8+ Regulatory T Lymphocytes and Their Specific Intervention in Graft-versus-Host and Infectious Diseases, Autoimmunity, and Cancer”, Journal of Immunology Research, vol. 2018, Article ID 3758713, 16 pages, 2018. https://doi.org/10.1155/2018/3758713

Figure 2

Schematic representation of the mechanisms of immune suppression of CD8⁺ T_regs in SLE. A. CD8⁺ T_regs secrete cytokines/chemokines such as TGFβ, IL-10, and CCL4 that suppress immune responses. B. CD8⁺ T_regs can also suppress in a cell contact-dependent fashion that may depend on the surface expression of membrane-bound TGFβ (and/or CTLA-4). C. MHC class I-restricted CD8⁺ T_regs are capable to kill activated CD4⁺ T effector (T_eff) cells that express Qa-1/HLA-E. D. CD8⁺ T_regs can render APCs tolerogenic by downregulating co-stimulatory molecules such as CD80 and CD86, and upregulating inhibitory receptors such as ILT3 and ILT4. APC, antigen presenting cells; ILT, Ig-like transcript; SLE, systemic lupus erythematosus; and T_regs, T regulatory cells. Modified with permission from Ref # 20, Dinesh RK et al, Autoimmun Rev. 2010 Jun;9(8):560-8. Copyright, 2010, Elsevier.