Natural killer T cells

CD1d-restricted T cell activation by nonlipidic small molecules. Van Rhijn, I. et al. Proc. Natl Acad. Sci. USA 101, 13578–13583 (2004).

The natural killer T (NKT)-cell population contains cells expressing a diverse repertoire of T-cell receptors (TCRs), in addition to those expressing invariant Vα14 or Vα24 TCRs in mice and humans, respectively. Van Rhijn et al. derived a human CD1d-restricted T-cell line expressing a Vα2/Vβ21 TCR. This T-cell line was shown to be specific for small sulphated polyaromatic structures, and the magnitude of the T-cell response induced by these structures varied depending on their pattern of hydroxylation and methylation. Although these antigens are not physiological, they have similar chemical features to several commonly used antibiotics and anti-inflammatory drugs known to induce strong hypersensitivity reactions in humans, leading the authors to suggest that these drugs might function as NKT-cell antigens.

Cytokines

Itch E3 ligase-mediated regulation of TGF-β signaling by modulating Smad2 phosphorylation. Bai, Y. et al. Mol. Cell 15, 825–831 (2004).

Transforming growth factor-β (TGF-β) receptor signal-transduction pathways are known to involve protein ubiquitylation. In this study, using mouse embryonic fibroblasts deficient in the E3 ubiquitin ligase ITCH, the authors show that the TGF-β-induced arrest in cell growth is markedly reduced in the absence of ITCH. This correlated with decreased phosphorylation of SMAD2, a signal transducer activated by the TGF-β receptor. Further analysis indicated that ITCH interacts with SMAD2 and mediates its ubiquitylation, and that ITCH, SMAD2 and the TGF-β receptor associate in cells stimulated with TGF-β. Together, these observations led the authors to conclude that ITCH positively regulates TGF-β-induced SMAD2 phosphorylation by enhancing the interaction of SMAD2 with the TGF-β receptor in a ubiquitylation-dependent manner.

B-cell signalling

Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling. Mecklenbräuker, I. et al. Nature 8 September 2004 (doi:10.1038/nature02955).

Serine/threonine protein kinase C-δ (PKC-δ)-deficient mice develop a lupus-like autoimmune phenotype similar to that of mice transgenic for the B-cell survival factor BAFF (B-cell activating factor). To investigate the mechanism of disease in PKC-δ-deficient mice, the authors studied the effects of BAFF-mediated signals on PKC-δ deficiency and observed that, in the absence of PKC-δ, B cells were unresponsive to the effects of BAFF-receptor signalling. Further analysis revealed that nuclear localization of PKC-δ had a pro-apoptotic effect on B cells and that recombinant BAFF prevented nuclear accumulation of PKC-δ. Together, these data indicate the existence of a novel pathway by which BAFF regulates B-cell survival — preventing PKC-δ localization to the nucleus.