Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to "self" leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

Keywords: Autoimmune disease; SLE; T cells; autoimmunity; signaling.

Figure 1

Aberrant signaling in systemic lupus erythematosus (SLE) T cells. SLE T cells are characterized by multiple aberrant signaling pathways, such as decreased CD3ζ, activated PI3K-Akt-mTORC1 pathway, Rho associated protein kinase (ROCK), calcium/calmodulin kinase IV (CaMKIV), and protein phosphatase 2A (PP2A). These are associated with abnormalities in T cell differentiation and production of proinflammatory cytokines such as IL-17 and decreased production of vital cytokines such as IL-2. Molecules aberrantly increased or decreased in SLE are indicated in red and blue boxes, respectively, and molecules that are potential therapeutic targets are in green circles.