Structure

Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Skiniotis, G. et al. Nature Struct. Mol. Biol. 15 May 2005 (10.1038/nsmb941)

Structural analysis of the cytokine-binding domains of gp130 (glycoprotein 130), interleukin-6 (IL-6) and the α-chain of the IL-6 receptor (IL-6Rα) indicated that this trimolecular complex dimerizes for signalling to occur. However, the membrane-proximal domains of gp130 were predicted to extend away from each other, rather than enter the membrane in close proximity as would be expected for signalling to occur. Skiniotis et al. visualized the conformation of the extracellular portion of gp130 (the cytokine-binding and membrane-proximal domains) complexed with IL-6 and IL-6Rα and observed that the gp130 molecules are bent such that the membrane-proximal domains interact close to the membrane. The authors suggest that this enables activation of intracellular signalling and that bending of the gp130 molecules might occur as a conformational transition when ligand binds.

Dendritic cells

Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. Galibert, L. et al. J. Biol. Chem. 280, 21955–21964 2005)

Galibert et al. set out to identify markers of dendritic cell (DC) subsets that are conserved across species. A single-chain antibody fragment (scFv) that specifically labels human BDCA3+ DCs was isolated using a whole-cell-panning phage-display approach. When expressed as an Fc fusion protein, this scFv also bound mouse splenic CD11c+CD11b−CD8α+ DCs. The scFv target was shown to be nectin-like protein 2 (NECL2), and its ligand was identified as class-I-restricted T-cell-associated molecule (CRTAM), which is expressed by activated CD8+ T cells. CRTAM–NECL2 interactions induced increased expression of interleukin-22 mRNA by the activated CD8+ T cells, leading the authors to suggest that this conserved interaction probably contributes to DC–T-cell crosstalk.

Lymphocyte signalling

Cytokine-driven cell cycling is mediated through Cdc25A. Khaled, A. R. et al. J. Cell Biol. 31 May 2005 (10.1083/jcb. 2004 09099)

Lymphocytes are known to require cytokine-mediated signals, such as those provided by interleukin-7 (IL-7) or IL-3, for both survival and proliferation, but until now, little has been known about the cytokine-driven proliferation pathway. This study shows that cytokine signals are required to prevent p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and degradation of the phosphatase CDC25A (cell-division cycle 25A). CDC25A, in turn, dephosphorylates cyclin-dependent kinases such as CDK2, which promotes association with cyclin E, phosphorylation of the cell-cycle inhibitor retinoblastoma-susceptibility protein and entry to the cell cycle. Cytokines, therefore, seem to protect lymphocytes from a stress response that involves activation of the stress kinase p38 MAPK by cytokine withdrawal.