Genetic Variations Controlling Regulatory T Cell Development and Activity in Mouse Models of Lupus-Like Autoimmunity

Abstract

Immune homeostasis is a constant balancing act between effector T cells and regulatory T cells defined by Foxp3 expression, the transcription factor that drives their differentiation and immunosuppressive activity. Immune homeostasis is altered when Treg cells are not generated or maintained in sufficient numbers. Treg cells rendered unstable by loss of Foxp3 expression, known as ex-Treg cells, gain pro-inflammatory functions. Treg cells may also become dysfunctional and lose their suppressive capabilities. These alterations can cause an imbalance between effector and regulatory subsets, which may ultimately lead to autoimmunity. This review discusses recent studies that identified genetic factors that maintain Treg cell stability as well as preserve their suppressive function. We focus on studies associated with systemic lupus erythematosus and highlight their findings in the context of potential therapeutic gene targeting in Treg cells to reverse the phenotypic changes and functional dysregulation inducing autoimmunity.

Lupus susceptibility gene Pbx1 controls the development, stability, and function of regulatory T cells via Rtkn2 expression

“…Inflammatory cytokines that are common contributors to lupus pathogenesis, such as IL-6 or type I IFN, impair T reg functions ( 57 , 58 ). There is also evidence for a genetic basis for impaired T reg cells in lupus ( 8 ), including the Esrrg and Pbx1 genes in the Sle1 murine susceptibility locus, which has the strongest linkage to lupus nephritis and directs the production of autoantibodies through intrinsic defects in B and CD4 + T cells ( 59 , 60 ). The low expression of Esrrg in T cells corresponds to the Sle1c2 locus ( 61 ), and Esrrg deletion in T reg cells impaired their suppressive function and led to the expansion of autoreactive inflammatory Teff cells ( 62 ).…”

“…Systemic lupus erythematosus (SLE) is an autoimmune disease in which T reg dysfunctions have been documented in patients with either decreased numbers ( 6 ), suppressive functions, or both ( 7 ), as well as in mouse models of the disease. Moreover, the T reg -specific deletion or overexpression of several genes that impair T reg functions resulted in lupus-like phenotypes in murine models ( 8 ).…”

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

“…Natural CD4+ Tregs are rendered unstable by loss of FoxP3 expression, which can ultimately lead to autoimmunity. FoxP3 mutation has been reported as a rare X-linked recessive (IPEX) syndrome with aggressive autoimmunity with the clinical feature of immune dysregulation, polyendocrinopathy, and enteropathy in humans ( 9 , 20 ). Epigenetic modifications, which can be influenced by both genetic and environmental factors, also impact T-cell function in SLE.…”