T-cell Signalling

Regulation of ZAP-70 activation and TCR signalling by two related proteins, Sts-1 and Sts-2. Carpino, N. et al. Immunity 20, 37–46 (2004)

This paper describes a novel protein — suppressor of T-cell receptor (TCR) signalling 2 (Sts2) — with homology to Sts1. Although Sts2-deficient mice have no haematopoietic lineage defects, in vitro TCR crosslinking led to hyperproliferation of Sts1/Sts2-deficient T cells, and increased cytokine production. This enhanced responsiveness of Sts1/Sts2-deficient T cells was associated with increased phosphorylation of several TCR-signalling components, including ZAP70, LAT, SLP76 and MAPK, and Sts1/Sts2-deficient mice showed enhanced susceptibility to experimental autoimmune encephalomyelitis. This study establishes a redundant role for Sts1 and Sts2 as negative regulators of TCR signalling, and future work will investigate their mechanism of action.

Dendritic Cells

IL-10-conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals. Nolan, K. F. et al. J. Immunol. 172, 2201–2209 (2004)

In this study, Nolan et al. identified a novel ligand for CXC-chemokine receptor 2 (CXCR2), dendritic cell (DC) inflammatory protein 1 (DCIP1). DCIP1 has homology with mouse CXC-chemokine ligand 2 (CXCL2) and, like CXCL2, DCIP1 mRNA was rapidly upregulated after lipopolysaccharide (LPS) stimulation of bone-marrow-derived DCs (BMDCs), indicating a role for DCIP1 early in inflammation. Similar to CXCL2, DCIP1 mediated chemotaxis of a CXCR2-expressing cell line in vitro and neutrophil recruitment in vivo. Treatment of BMDCs with interleukin-10 (IL-10) before LPS exposure enhanced their ability to upregulate the expression of DCIP1 and other pro-inflammatory chemokines, although the induction of chemokines and receptors associated with adaptive immunity was impaired, indicating that IL-10-treated BMDCs are a phenotypically distinct BMDC population.

T-Cell Activation

Lipid raft proteins have a random distribution during localized activation of the T-cell receptor. Glebov, O. O. & Nichols, B. J. Nature Cell Biol. 8 February 2004 (doi: 10.1038/ncb1103)

Fluorescence resonance energy transfer (FRET), which can detect small clusters of molecules, was used to study the role of lipid-raft microdomains in T-cell synapse formation. Are components recruited through protein–protein interactions, or are they clustered in lipid rafts, which redistribute to the synapse? By expressing glycophosphatidylinositol (GPI)-linked FRET donor and acceptor proteins in Jurkat T cells, the authors showed that the distribution of lipid rafts (identified by the GPI-linked proteins) throughout the cell membrane was not altered by activation with CD3-specific antibody. It will now be necessary to determine whether physiological T-cell synapses also form without requiring lipid-raft redistribution.

Tolerance

AIRE functions as an E3 ubiquitin ligase. Uchida, D. et al. J. Exp. Med. 199, 167–172 (2004)

Autoimmune regulator (AIRE) has an important role in the generation of self-tolerance, as mutations of this gene result in a range of organ-specific autoimmune diseases. Previous studies have indicated that AIRE is a transcriptional activator for the expression of otherwise organ-specific antigens by medullary epithelial cells of the thymus. This study now indicates that AIRE might also function as an E3 ubiquitin ligase. AIRE contains two plant homeodomains (PHDs), which have recently been shown in other proteins to facilitate polyubiquitylation of target proteins. The authors show that the PHD1 of AIRE has E3 ligase activity, which is abolished by common disease-causing mutations. By contrast, PHD2 is responsible for transcriptional activation. It remains to be determined whether the E3 ligase activity modifies proteins in the AIRE-containing transcriptional complex or has an independent effect.

Tumour Immunity

Immune recognition of a human renal cancer antigen through post-translational protein splicing. Hanada, K. et al. Nature 427, 252–256 (2004)

This study indicates a new mechanism by which protein epitopes can be generated for presentation on MHC class I molecules. A human cytotoxic T lymphocyte (CTL) clone isolated from a renal cell carcinoma that overexpresses fibroblast growth factor 5 (FGF5) was tested for recognition of HLA-A3-expressing cells transfected with various truncated and internally deleted forms of FGF5. Surprisingly, the CTLs were shown to recognize an FGF5 peptide consisting of five amino-terminal amino acids and four carboxy-terminal amino acids. Further experiments showed that this epitope was created by post-translational protein splicing — the first demonstration of such a process occurring in vertebrates. The ability of the immune system to recognize non-contiguous peptide sequences could potentially enhance immune surveillance.

T-cell Responses

GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Pai, S.-Y. et al. Proc. Natl Acad. Sci. USA 101, 1993–1998 (2004)

These authors have used the conditional knockout of Gata3 in mice to confirm the role of this transcription factor in the commitment of naive CD4+ T cells to the T helper 2 (TH2) lineage. In previous studies, overexpression of Gata3 in developing TH1 cells was sufficient to drive TH2-type cytokine expression. However, confirmation of the physiological role of Gata3 has been lacking, as deletion of Gata3 results in an early block in T-lineage commitment. Conditional deletion of Gata3 in stage-3 double-negative thymocytes led to both CD4+ and CD8+ T cells that were unable to produce type-2 cytokines. Furthermore, the persistent expression of Gata3 was required for TH2 cells to maintain their appropriate cytokine production, indicating that Gata3 is required for both the development and active maintenance of TH2 cells.