Tumour immunity

DC–NK cell cross-talk as a novel CD4+ T cell-independent pathway for antitumour CTL induction. Adam, C. et al. Blood 15 Mar 2005 (10.1182/blood-2004-09-3775)

While assessing the ability of peptide-pulsed dendritic cells (DCs) to protect against tumour-cell challenge, Adam et al. observed that non-pulsed, syngeneic, bone-marrow-derived DCs protected mice against challenge with A20 B-cell lymphoma cells. Protection was natural killer (NK)-cell dependent, and surprisingly, protected mice showed A20-specific CD8+ T-cell-dependent immunological memory. Such memory was also observed after immunization with CD40-deficient DCs, indicating that CD8+ T-cell activation occurred independently of CD4+ T-cell help. Because NK cells secreted interferon-γ (IFN-γ) in response to CD40-deficient DCs and because this was required for CD8+ T-cell activation, the authors suggest that immunization with DCs can activate NK cells to produce IFN-γ, which then activates endogenous DCs to activate CD8+ T cells independently of CD4+ T-cell help.

Inflammation

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. Abeyama, K. et al. J. Clin. Invest. 14 Apr 2005 (1172/JCI200522782)

Abeyama et al. set out to investigate whether thrombomodulin (TM) — an endothelial-cell-specific membrane receptor that is an anticoagulant co-factor — also inhibits inflammation by sequestering pro-inflammatory mediators such as high-mobility group box 1 protein (HMGB1). They found that TM associates with HMGB1 through its amino (N)-terminal lectin-like domain (D1), which prevents HMGB1 from binding its receptor RAGE (receptor for advanced glycation end-products). Functional evidence to support their hypothesis was provided by the observation that both recombinant soluble human TM and a recombinant polypeptide corresponding to D1 inhibited HMGB1-induced activation of nuclear factor-κB and generation of reactive-oxygen species in vitro, as well as ultraviolet-light-induced cutaneous inflammation and lipopolysaccharide-induced lethality in vivo.

T-cell signalling

A ligand-induced conformational change in the T cell receptor associated with productive immune synapses. Risueño, R. M. et al. Blood 24 Mar 2005 (10.1182/blood-2004-12-4763)

There are two main models for the initiation of T-cell receptor (TCR) signalling: the clustering model, in which TCR signalling is initiated by TCR clustering, a model that is supported by the ability of antibodies to crosslink the TCR and stimulate signalling; and the conformational-change model. So far, structural studies have not provided much evidence to support a role for conformational change. In this study, Risueño et al. show that the antibody APA1/1 detects a conformational change in the cytoplasmic tail of the CD3ε chain following TCR ligation. This change was only detectable when the TCR was stimulated with an agonist peptide in the context of MHC and not with a partial agonist peptide, and the change was detectable both in vitro and in vivo.