T-cell signalling

A novel E3 ubiquitin ligase TRAC-1 positively regulates T cell activation. Zhao, H. et al. J. Immunol. 174, 5288–5297 (2005)

When screening for molecules involved in T-cell activation downstream of T-cell receptor (TCR) ligation, Zhao et al. identified a cDNA encoding a carboxy (C)-terminally truncated form of an uncharacterized protein. As the full-length protein contained a RING (really interesting new gene)-finger domain at its amino terminus, the authors named the new molecule T-cell RING protein identified in activation screen 1 (TRAC1). Consistent with the presence of a RING-finger domain, TRAC1 had RING-finger-dependent E3 ubiquitin ligase activity. And endogenous TRAC1 functioned as a positive regulator of T-cell activation downstream of TCR ligation. By contrast, C-terminally truncated TRAC1 inhibited TCR-induced CD69 upregulation, indicating the importance of this domain for TRAC1 function.

Mast cells

Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim. Moller, C. et al. Blood 26 Apr 2005 (10.1182/blood-2004-12-4792)

Möller et al. investigated the molecular mechanisms by which stem-cell factor (SCF) promotes mast-cell survival. SCF induced phosphorylation of forkhead box O3A (FOXO3A) in bone-marrow-derived cultured mast cells (BMCMCs). Consistent with phosphorylation of FOXO3A resulting in its inactivation, SCF prevented expression of BIM (B-cell lymphoma 2 (BCL-2)-interacting mediator of cell death), a pro-apoptotic member of the BCL-2 family, the gene encoding which is a FOXO3A target. Further analysis indicated that SCF also induced phosphorylation of BIM, which has been linked with proteasome-mediated degradation. Together with the observation that Bim−/− BMCMCs showed increased viability following SCF withdrawal, these data characterize a mechanism for SCF-regulated mast-cell survival.

Allergy

Antigen-specific CD4+ T cells drive airway smooth muscle remodeling in experimental asthma. Ramos-Barbon, D. et al. J. Clin. Invest. 2 May 2005 (10.1172/JCI19711)

The relationship between airway smooth muscle (ASM) growth and T-cell-mediated airway inflammation in asthma is poorly understood. So, to study this, antigen-specific CD4+ T cells were isolated from sensitized rats and transfected with green fluorescent protein before being transferred to naive recipients. After repeated antigen challenge, the transferred cells induced a marked inflammatory response with CD4+ T-cell infiltration in the airways. The infiltrating T cells co-localized with ASM cells and led to increased ASM growth. This T-cell–myocyte crosstalk was also evident in vitro: ASM cells proliferated on direct contact with activated CD4+ T cells, and reciprocally, activation-induced T-cell death was inhibited in a contact-dependent manner. These data implicate CD4+ T cells as promoters of pathology in asthma.