title: Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice.
abstract: Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self-tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)-2 critically maintains homeostasis of regulatory T cells (T(reg)) and effector T cells in the periphery. Previously, we identified the cAMP-responsive element modulator α (CREMα) as a major factor responsible for decreased IL-2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over-expresses CREMα in T cells (CD2CREMαtg), we provided in-vivo evidence that CREMα indeed suppresses IL-2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas(-/-) CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas(-/-) mice. This was accompanied by a massive expansion of double-negative (DN) T cells, enhanced numbers of interferon (IFN)-γ-producing T cells and reduced percentages of T(regs). Treatment of FVB/Fas(-/-) CD2CREMαtg mice with IL-2 restored the percentage of T(regs) and reversed increased IFN-γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL-2 in vivo.
authors: Department of Pediatrics, RWTH Aachen, Aachen, Germany.|IZKF Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors: K
authors: K
authors: Ohl
authors: Department of Pediatrics, RWTH Aachen, Aachen, Germany.
authors: A
authors: A
authors: Wiener
authors: Department of Pediatrics, RWTH Aachen, Aachen, Germany.
authors: A
authors: A
authors: Schippers
authors: Department of Pediatrics, RWTH Aachen, Aachen, Germany.
authors: N
authors: N
authors: Wagner
authors: Department of Pediatrics, RWTH Aachen, Aachen, Germany.
authors: K
authors: K
authors: Tenbrock
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis* / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D019014:fas Receptor / Q000235:genetics
chemical_list: C491899:Fas protein, mouse; D007074:Immunoglobulin G; D007376:Interleukin-2; D019014:fas Receptor; D051786:Cyclic AMP Response Element Modulator; D007371:Interferon-gamma
keywords: CREM; IL-2; SLE; regulatory T cells