Schnurri-2 Controls Memory Th1 and Th2 Cell Numbers In Vivo

Abstract

Schnurri-2 (Shn-2) is a large zinc-finger containing protein, and it plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient CD4 T cells, the activation of NF-κB was up-regulated and their ability to differentiate into Th2 cells was enhanced. We herein demonstrate that Th1 and Th2 memory cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. Even a week after the transfer of effector Th1/Th2 cells into syngeneic mice, a dramatic decrease in the number of Shn-2-deficient donor T cells was detected particularly in the lymphoid organs. The transferred Shn-2-deficient Th1/Th2 cells express higher levels of the activation marker CD69. No significant defect in the BrdU incorporation in the Shn-2-deficient transferred CD4 T cells was observed. The numbers of apoptotic cells were selectively higher in Shn-2-deficient donor Th1/Th2 cell population. Moreover, Shn-2-deficient effector Th1 and Th2 cells showed an increased susceptibility to cell death in in vitro cultures with increased expression of FasL. Transfer of Th2 effector cells over-expressing the p65 subunit of NF-κB resulted in a decreased number of p65-expressing cells in the lymphoid organs. As expected, T cell-dependent Ab responses after in vivo immunization of Shn-2-deficient mice were significantly reduced. Thus, Shn-2 appears to control the generation of memory Th1/Th2 cells through a change in their susceptibility to cell death.

Initiation and maintenance of Th2 cell identity

“…In a series of studies on the role of Shn-2 in the CD4 T cell immunity, we have found that Shn-2 is required for the generation of sufficient numbers of both memory Th1 and Th2 cells [42 ]. The expression levels of Shn-2 were high in naïve CD4 T cells, but they were decreased after TCR stimulation, and increased again in memory Th1/ Th2 cells, particularly in memory Th2 cells.…”

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3

“…The Schnurri family of large zinc-finger proteins consists of three mammalian homologs (Shn1, Shn2, and Shn3) that are present in numerous tissue and cell types, including those within the skeleton (10)(11)(12)(13)(14)(15)(16)(17). Recent analysis of mice deficient in individual Shn genes has uncovered a novel role for this protein family in regulating skeletal remodeling.…”

Dampening of death pathways by schnurri-2 is essential for T-cell development

“…Schnurri (Shn) family proteins are large zinc-finger containing proteins that regulate morphogenesis in C. elegans and Drosophila 6,7. In vertebrates, they influence bone formation, adipogenesis, and memory T cell survival8–10. Interestingly, Shn2 −/− mice have very few post-selection DP thymocytes or mature single positive (SP) thymocytes but how Shn2 regulates T cell development has remained a mystery (Fig.…”