Signalling

Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-κB activation in muramyl dipeptide recognition. Barnich, N. et al. J. Cell Biol. 170, 21–26 (2005)

Mutations in nucleotide-binding oligomerization domain protein 2 (NOD2) are associated with Crohn's disease. When expressed by intestinal epithelial cell lines, ligation of the Crohn's-disease-associated 3020insC NOD2 mutant does not activate nuclear factor-κB (NF-κB). In this study, wild-type NOD2 was detected in the cytoplasm, in vesicles and associated with the membrane of intestinal epithelial cell lines, whereas the 3020insC NOD2 mutant was present only in the cytosol and in vesicles. A panel of NOD2 deletion mutants was used to show that the last six amino acids of NOD2 are necessary, but not sufficient, to target NOD2 to the membrane. Furthermore, for these mutants, membrane targeting correlated with the ability of the protein to activate NF-κB.

Haematopoiesis

NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Zhu, J. et al. Proc. Natl Acad. Sci. USA 102, 11728–11733 (2005)

Nuclear transcription factor Y (NF-Y) is a trimer, the activity of which is regulated by the level of expression of the NF-Ya subunit. Zhu et al. set out to investigate the role of NF-Y in haematopoietic stem cell (HSC) self-renewal and differentiation. NF-Ya was most highly expressed by the most primitive HSCs, and overexpression of NF-Ya in these cells induced the expression of many genes encoding proteins that influence HSC self-renewal and differentiation. When transferred to lethally irradiated mice, larger numbers of primitive HSCs accumulated in recipients of HSCs that were engineered to express NF-Ya than in recipients of control HSCs. Similar expansion of primitive HSC numbers was seen in vitro. Therefore, the authors suggest that NF-Ya is a potent regulator of HSC self-renewal.

Tolerance

A critical role for the programmed death ligand 1 in fetomaternal tolerance. Guleria, I. et al. J. Exp. Med. 202, 231–237 (2005)

What prevents the maternal immune system from rejecting a fetus, which expresses paternally inherited alloantigens, is poorly understood. Using a mouse model of allogeneic pregnancy, this study shows that the inhibitory T-cell co-stimulatory molecule programmed death ligand 1 (PDL1) has a crucial role in conferring fetomaternal tolerance. Pregnant mice treated with antibody specific for PDL1, but not those treated with control antibody, had increased rates of fetal rejection and reduced litter sizes. This rejection was T-cell mediated, because mice lacking T and B cells, but not B-cell-deficient mice, had normal pregnancies when treated with PDL1-specific antibody. The numbers of interferon-γ-producing cells were increased systemically and in the placenta of PDL1-specific-antibody-treated mice, indicating that blockade of this inhibitory molecule promotes fetal rejection by clonal expansion of alloreactive T helper 1 cells.