RESEARCH HIGHLIGHTS© 2007 Nature Publishing Group http://www.nature.com/natureimmunology

New directions for ISImmune synapses form after cognate antigen recognition by T cells.
In CellCell, Dustin and colleagues show that such immune synapses
in naive T cells demonstrate dynamic activity and can transiently
reorient through the opposing activities of protein kinase C-θ (PKCθ) and WASP (the Wiscott-Aldrich syndrome protein). Neither PKC-θ
nor WASP is required for the formation of immune synapses, but
PKC-θ, which is present as punctae in the peripheral supramolecularactivation cluster, directs the relocation of the immune synapse. Tcells expressing PKC-θ form breaks in the symmetrical arrangementof their immune synapses and can translocate in the direction ofthe breaks. In contrast, WASP is needed to reform the symmetricalimmune synapse structure. In vivo imaging shows that PKC-θ isrequired for dynamic sampling of dendritic cell networks by T cells.
These data indicate that immune synapses are much more dynamic
structures than previously thought.
LAD
Cell 129, 773–785 (2007)

Advancing Aire expression
Expression of the transcription factor Aire in medullary TECs is essential
for deletion of developing thymocytes bearing T cell receptors specificfor tissue-restricted self antigens. In the Journal of Experimental Medicine,Anderson and colleagues identify a function for receptor activator ofNF-κB (RANK) signaling in the differentiation of Aire+ medullary TECs.
Aire is upregulated coincidentally with the appearance of the activation
marker CD80 on the surface of medullary TECs. CD80– medullary TECs
give rise to CD80+ medullary TECs, and passage through this precursor-product transition requires the presence of CD4+CD3– thymocytesthat resemble lymphoid tissue–inducer cells. Interaction between RANK
ligand on thymic lymphoid tissue–inducer cells and RANK on medullary
TECs sparks Aire expression, and RANK-deficient mice show autoimmunity and defective expression of Aire and tissue-restricted self antigens in
the thymus. The molecular mechanisms linking RANK and expressionof Aire remain to be identified.
CBJ. Exp. Med. (14 May 2007) doi:10.1084/jem.20062497

LFA-1 redistributes Ras
The GTPase Ras functions in pathways that can lead to oppositeeffects, such as positive and negative selection of T cells. In
Nature Cell Biology
Biology, Philips and colleagues demonstrate that‘compartmentalized’ signaling by Ras in T cells is regulated by
the integrin LFA-1. It is known that palmitoylated Ras traffics
between the Golgi apparatus and the plasma membrane and that
T cell receptor stimulation, with or without costimulation, induces
Ras activation only at the Golgi. Here, live-cell imaging of T cells
shows that stimulation of both the T cell receptor and LFA-1 arerequired for the activation of Ras at the Golgi and the plasma
membrane; both require the exchange protein Ras-GRP1, whereas
activation at the Golgi also requires phosopholipase C. In addition,that LFA-1 signaling leads to increased activity of diacylglycerol
and phospholipase D. Thus, ‘outside-in’ LFA-1 signaling via
phospholipase D is required for activation of Ras at the plasma
membrane in T cells.
DCB
Nat. Cell Biol. 9, 713–719 (2007)
Research highlights written by Christine Borowski, Douglas C. Braaten andLaurie A. Dempsey

NATURE IMMUNOLOGY VOLUME 8 NUMBER 7 JULY 2007Thymic proteasomes
Proteasomes initiate the cleavage of peptides destined for presentation on
major histocompatibility complex class I molecules. In Science, Murata etal. identify a thymic-specific proteasome subunit called β5t, whose expression is confined to cortical thymic epithelial cells (TECs). This subunit
seems to be incorporated instead of the prototypical β5 subunit. As a result,the chymotrypsin-like catalytic activity of β5t-containing proteasomes isdecreased, thereby reducing the number of peptides with hydrophobic
residues at their carboxyl termini. Mice lacking β5t have normal thymicarchitecture and development of CD4+ single-positive thymocytes but
have fewer CD8+ single-positive thymocytes. Notably, the authors showthat major histocompatibility complex class I molecules are expressed insimilar abundance on β5t-deficient and wild-type cortical TECs. Theseresults show that β5t alters the thymic peptide repertoire presented toCD4+CD8+ double-positive thymocytes and can profoundly influence
the positive selection of CD8+ single-positive thymocytes.
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Science 316, 1349–1353 (2007)

First things first
The transcription factors Blimp-1, Pax5, IRF4 and XBP-1 all seemto influence the differentiation of antibody-secreting cells (ASCs).
In Immunity
Immunity, Nutt and coworkers align distinct transcription factors
with discrete stages of ASC development. Mice expressing a green
fluorescent protein (GFP) reporter in place of functional Blimp-1
have smaller but nevertheless detectable amounts of serum andmucosal immunoglobulins. GFP upregulation occurs after
T cell–dependent or T cell–independent B cell stimulation, evenin the absence of Blimp-1. However, subsequent expression of theASC marker syndecan-1 requires Blimp-1. Blimp-1-deficient GFP+syndecan-1-positive ‘pre-plasmablasts’ produce immunoglobulins
and have higher expression of XBP-1 and lower expressionof Pax5 than do naive B cells. These data indicate that Pax5
downregulation occurs before the induction of Blimp-1 expression
and characterize an intermediate stage of ASC differentiation. The
molecular mechanisms enforcing suppression of Pax5 expression
and function, which seem to be post-translational, remain to bedefined precisely.
CBImmunity 26, 1–12 (2007)

TLR2 triggers TH1
Toll-like receptors (TLRs), essential for innate immunity, are also expressedon T cells and can modulate naive T cell activation. In the Journal ofImmunology, Saito and colleagues investigate whether TLR stimulationinfluences the biology of differentiated T helper cells. First evaluating
T helper type 1 (TH1) cells, they find that among all TLRs, only stimulationof TLR2 results in the production of interferon-γγ (IFN-γγ). Although ligandsfor TLR9 and TLR2 can act in synergy with antibody to CD3 to activatenaive T cells, only TLR2 ligands stimulate TH1 cells. IFN-γγ produced by
the TH1 cells is enhanced substantially by interleukin 2 or interleukin 12.
In addition to producing IFN-γ,γγ, stimulated TH1 cells upregulate CD69 andCD70, the survival factors c-Myc and Bcl-xL and, relative to that of TH1 cells
not stimulated by TLR2 ligands, have strong and sustained activation of
the transcription factor NF-κB and the Jnk, p38 and Erk kinases. Although
TH1 and TH2 cells have equivalent expression of TLR2, ligands for TLR2
and all other TLRs fail to stimulate TH2 cells. Thus, stimulation of TLR2induces strong TH1 responses through the production of T cell–derived
IFN-γγ and innate immune cell–derived interleukin 12.
DCBJ. Immunol. 178, 6715–6719 (2007)

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