In Brief

T-cell activation

A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Maldonado, R. A. et al. Nature 431, 527–532 (2004).

The immunological synapse forms at the T cell–antigen-presenting cell interface and is important for optimal T-cell activation. In this study, activation of naive T cells with peptide-loaded dendritic cells (DCs) induced T-cell receptor and interferon-γ receptor (IFN-γR) co-localization at the T cell–DC interface. IFN-γR synapse polarization occurred after activation of naive T cells from C57BL/6 mice (which are T_H1-response prone), but polarization was only partial for naive T cells from BALB/c mice (which are T_H2-response prone). Furthermore, IL-4 inhibited IFN-γR synapse polarization, so the authors suggest that IL-4 levels may determine T-cell lineage commitment by regulating IFN-γR migration to the synapse.

Immunotherapy

Targeted deletion of T-cell clones using α-emitting suicide MHC tetramers. Yuan, R. R. et al. Blood 104, 2397–2402 (2004).

Fluorescently labelled peptide–MHC class I tetramers are used to detect peptide-specific CD8⁺ T cells. Yuan et al. generated tetramers composed of three peptide-bound MHC class I molecules and a radioisotope. Multimers containing the γ-emitting isotope ¹¹¹In and the LMP1 peptide from the Epstein–Barr virus latency membrane protein were used to show that radiolabelled tetramers specifically bind their cognate CD8⁺ T cells. Using LMP1 peptide–MHC multimers labelled with ²²⁵Ac (an α-emitting radioisotope), the authors were able to show specific killing of LMP1-specific CD8⁺ T cells. Specific killing of CD8⁺ T cells that recognize the listeriolysin-derived peptide LLO_91–99 from Listeria monocytogenes was also shown using ²²⁵Ac-labelled LLO_91–99–MHC multimers. Further studies using 'suicide' tetramers in vivo could allow the generation of T-cell-selective therapies for autoimmunity.

Signalling

Human Tribbles, a protein family controlling mitogen-activated protein kinase cascades. Kiss-Toth, E. et al. J. Biol. Chem. 279, 42703–42708 (2004).

Using an assay to identify proteins that mediate inflammatory cytokine signalling, Kiss-Toth et al. found a human homologue of the Drosophila melanogaster gene tribbles. Database searching identified two other homologues. Overexpression of either TRB1 or TRB3 inhibited activation of the transcription factor AP1 mediated by the mitogen-activated protein kinase kinase kinase (MAPKKK) MEKK1. Further analysis indicated that TRB3 acts downstream of MEKK1 and that TRB1 associates with the MAPKKs MEK1 and MAPKK4, whereas TRB3 interacts with MEK1 and MAPKK7. Downstream of this, low levels of TRB3 had distinct effects on the three sets of effector MAPKs: it increased both JNK and ERK activity but inhibited p38 activity. By contrast, high levels of TRB3 inhibited JNK, ERK and p38 activity. So, this study indicates that TRBs regulate MAPK activity by binding to MAPKKs.