BALB/C mice lacking Act1 develop systemic autoimmunity resembling systemic lupus erythematosus Cell Cycle inhibitor (SLE) and Sjögren’s syndrome (SjS). SLE and SjS are characterized by anti-nuclear IgG autoantibody (ANA-IgG) production and inflammation

of peripheral tissues. As autoantibody production can occur in a T-cell dependent or T-cell independent manner, we investigated the role of T-cell help during Act1-mediated autoimmunity. Act1-deficiency was bred onto C57Bl/6 (B6.Act1−/−) mice and B6.TCRβ−/−TCRδ−/−Act1−/− (TKO) mice were generated. While TCRβ/δ-sufficient B6.Act1−/− mice developed splenomegaly and lymphadenopathy, hypergammaglobulinemia, elevated levels of ANA-IgG, and kidney pathology, TKO mice failed to develop any such signs of disease. Neither B6.Act1−/− nor TKO mice developed SjS-like disease, suggesting that epigenetic interactions on the BALB/C background

are responsible for this phenotype in BALB/C.Act1−/− mice. Interestingly, BAFF-driven transitional B-cell abnormalities, previously reported in BALB/C.Act1−/− mice, were intact in B6.Act1−/− mice and largely independent of T cells. In conclusion, T cells are necessary for the development of SLE-like disease in B6.Act1−/− mice, but not BAFF-driven transitional B-cell differentiation. Act1 (Traf3ip2, Ciks) is a negative regulator of CD40 and B-cell activation factor of the TNF family (BAFF)-receptor mediated signaling [1]. As such, B cells from Act1-deficient BALB/C mice and from B-cell-specific Act1-deficient mice (CD19-CRE+/−Act1−/fl) display increased survival in response to anti-CD40 LEE011 mouse antibody or BAFF (also known as Blys, THANK) treatment [1, 2]. BALB/C.Act1−/− mice develop signs of systemic Ponatinib autoimmunity including splenomegaly,

lymphadenopathy and elevated serum anti-nuclear autoantibodies (ANA) starting as early as 3–4 weeks of age [1]. Likewise, both BAFF and CD40L transgenic mice have been shown to develop autoimmunity characterized by spontaneous B-cell activation and autoantibody production [3-5]. BAFF signaling is essential for B-cell maturation and survival as the immature T1 cells differentiate to transitional T2 and T3 B cells in the spleen (reviewed in [6]). In addition, it has been speculated that BAFF may function to maintain the mature pool of B cells [7]. The control of transitional B-cell differentiation is key to the elimination of potentially autoreactive B cells, and deficiency of Act1 in B cells lowers the threshold for B-cell elimination resulting in increased numbers of circulating mature autoreactive B cells [1, 2, 8]. Despite this, previous studies found that some autoantibody production is still measurable in Act1−/−BAFF−/− mice [1], suggesting that among the few B cells that effectively develop in the absence of BAFF signaling a population of autoreactive B cells remain. Act1 is recruited to the CD40 receptor upon binding of CD40 ligand (CD40L, CD154) [1, 9].