期刊
JOURNAL OF IMMUNOLOGY
卷 206, 期 8, 页码 1719-1728出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2001266
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资金
- Foundation for the National Institutes of Health [R01 AI136924]
The study reveals that an increase in the PP2A regulatory subunit PPP2R2A in T cells from patients with systemic lupus erythematosus enhances ROCK activity, leading to increased Th1 and Th17 cell differentiation, while deficiency of PPP2R2A reduces this differentiation and alleviates autoimmunity.
Protein phosphatase 2A (PP2A) composed of a scaffold subunit, a catalytic subunit, and multiple regulatory subunits is a ubiquitously expressed serine/threonine phosphatase. We have previously shown that the PP2A catalytic subunit is increased in T cells from patients with systemic lupus erythematosus and promotes IL-17 production by enhancing the activity of Rho-associated kinase (ROCK) in T cells. However, the molecular mechanism whereby PP2A regulates ROCK activity is unknown. In this study, we show that the PP2A regulatory subunit PPP2R2A is increased in T cells from people with systemic lupus erythematosus and binds to, dephosphorylates, and activates the guanine nucleotide exchange factor GEF-H1 at Ser(885), which in turn increases the levels of RhoA-GTP and the activity of ROCK in T cells. Genetic PPP2R2A deficiency in murine T cells reduced Th1 and Th17, but not regulatory T cell differentiation and mice with T cell-specific PPP2R2A deficiency displayed less autoimmunity when immunized with myelin oligodendrocyte glycoprotein peptide. Our studies indicate that PPP2R2A is the regulatory subunit that dictates the PP2A-directed enhanced Th1 and Th17 differentiation, and therefore, it represents a therapeutic target for pathologies linked to Th1 and Th17 cell expansion.
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