[Show abstract][Hide abstract] ABSTRACT: NF-κB-inducing kinase (NIK) plays critical roles in the development of lymph nodes and Peyer's patches, and microarchitecture of the thymus and spleen via NF-κB activation. Alymphoplasia (aly/aly) mice have a point mutation in the NIK gene that causes a defect in the activation of an NF-κB member RelB. Here, we developed a novel method to determine the aly mutation by genetic typing using PCR. This method facilitated the easy establishment of a congeneic aly/aly mouse line. Indeed, we generated a mouse line with aly mutation on a BALB/cA background (BALB/cA-aly/aly). BALB/cA-aly/aly mice showed significant splenomegaly with extramedullary hemopoiesis, which was not significant in aly/aly mice on a C57BL/6 background. Interestingly, the splenomegaly and extramedullary hemopoiesis caused by the aly mutation was gender-dependent. These data together with previous reports on extramedullary hemopoiesis in RelB-deficient mice suggest that NIK-RelB signaling may be involved in the suppression of extramedullary hemopoiesis in adult mice.
Preview · Article · Nov 2011 · Biochemical and Biophysical Research Communications
[Show abstract][Hide abstract] ABSTRACT: Regulatory T cells (Tregs), a subset of CD4(+) helper T cells, are crucial for immunological self-tolerance. Defect in development or function of Tregs results in autoimmune disease in human and mice. Whereas it is known that Tregs mainly develop in the thymus, the molecular mechanism underlying development of Treg is not fully understood. TRAF6-deficient mice showed a severe defect in the Treg development in thymus. In vitro fetal thymic organ culture experiments indicated that the defect is ascribed to the absence of TRAF6 in thymic cells. Moreover, mixed fetal liver transfer experiments revealed that the development of Foxp3(+) cells differentiated from Traf6(-/-) hematopoietic cells was specifically impaired in the thymus, indicating cell-intrinsic requirement for TRAF6 in the Treg development. On the other hand, TRAF6 is not required for the development of conventional CD4(+) T cell. In addition, TGFβ-dependent induction of Foxp3 in CD4(+) T cells in vitro was not impaired by the absence of TRAF6. Overall, our data indicate that TRAF6 plays an essential role on the commitment of immature thymocytes to thymic Tregs in cell-intrinsic fashion.
[Show abstract][Hide abstract] ABSTRACT: Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner. These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.