Psychoneuroimmunology

Affective style and in vivo immune response: neurobehavioral mechanisms. Rosenkranz, M. A. et al. Proc. Natl Acad. Sci. USA 5 September 2003 (DOI: 10.1073/pnas.1534743100)

This study looked at the correlation between physiological measures of negative emotion and the immune response to an influenza vaccine. Individuals with high comparative levels of activation of the right-hand side of the prefrontal cortex of the brain (at baseline and in response to a negative-emotion-inducing task) experience more intense negative emotions and are more likely to suffer from depression. These individuals produce lower antibody titres in response to vaccination. Antibody titres were also correlated with the eye-blink response to a task that induced negative emotions. Individuals with a larger eye-blink response (which indicates stronger negative emotion) produced lower antibody titres in response to vaccination. These studies help to clarify the link between depression and suppressed immune function.

Lymphocyte migration

The strategy of T cell–antigen-presenting cell encounter in antigen-draining lymph nodes revealed by imaging of initial T cell activation. Bajénoff, M. et al. J. Exp. Med. 198, 715–724 (2003)

Activated, antigen-loaded dendritic cells (DCs) migrate to the draining lymph node (LN), but how are they located by antigen-specific CD4+ T cells? Bajénoff et al. show that DCs that acquire antigen in the periphery preferentially accumulate in the paracortical region of the LN. More specifically, the DCs were close to the high endothelial venules (HEVs), where the initial stages of T-cell activation can be observed. The authors then showed that only antigen-specific T cells are retained in the proximity of the HEVs, indicating that DCs position themselves at the site of T-cell entry into the LN to maximize the chance of an immunogenic CD4+ T cell–DC interaction occurring.

Viral immunity

Self-inhibition of synthesis and antigen presentation by Epstein–Barr virus-encoded EBNA1. Yin et al. Science 301, 1371–1374 (2003)

The glycine–alanine repeat domain (GAr) of the Epstein–Barr virus-encoded protein nuclear antigen 1 (EBNA1) has been thought to prevent MHC class I presentation of EBNA1 peptides by inhibiting its proteasomal degradation. However, Yin et al. show that the GAr inhibits mRNA translation in cis, both in vitro and in vivo. The GAr sequence was most efficient at inhibiting translation when present at the amino-terminus of the protein, but its position did not influence its ability to inhibit proteasomal degradation, enabling the authors to show that GAr-mediated inhibition of translation and not proteasomal degradation is the mechanism by which EBNA1 evades MHC class I presentation. This is likely to prevent peptide production from defective ribosomal products (DRiPs) of EBNA1 translation — a key source of MHC class I presented peptides.

Antigen presentation

Characterization of the MHC class I crosspresentation pathway for cell associated antigens by human dendritic cells. Fonteneau, J. F. et al. Blood 21 August 2003 (DOI: 10.1182/blood-2003-06-1801)

This study is the first to characterize fully the MHC class I cross-presentation pathway in human dendritic cells (DCs) using a physiologically relevant system. The authors used apoptotic or necrotic monocytes infected with recombinant vaccinia virus expressing influenza A virus matrix protein 1 (MP). These were co-cultured with immature DCs, and the ability of the DCs to stimulate interferon-γ production by a MP-specific CD8+ T-cell clone was measured. By pre-incubating the DCs with various inhibitors that block the normal MHC class I presentation pathway, Fonteneau et al. showed that MP from apoptotic/necrotic cells is actively internalized by phagocytosis or macropinocytosis, pre-processed in endosomes by cathepsin D then enters the cytosol for processing by the proteasome and TAP-dependent entry into the endoplasmic reticulum and loading on to MHC class I molecules.

Immunogenetics

Parasite selection for immunogenetic optimality. Wegner, K. M. et al. Science 301, 1343 (2003)

Theoretical models have predicted that MHC diversity is a balance between evolutionary pressure to increase diversity for recognition of a greater number of potential pathogens and evolutionary pressure to decrease diversity to reduce the number of T cells that are deleted during negative selection. Wegner et al. have now provided experimental evidence for this theory. They infected groups of sticklebacks with common parasites and then measured the mean infection rate. The groups differed in terms of MHC diversity (number of MHC alleles), and the authors found that those fish with an intermediate number of alleles had the lowest infection rate and, therefore, the highest level of fitness.

Hiv

Directed expression of the HIV-1 accessory protein Vpu in Drosophila fat-body cells inhibits Toll-dependent immune responses. Leulier, F. et al. EMBO reports 12 September 2003 (DOI: 10.1038/sj.embor.embor936)

HIV-1 expresses various accessory proteins that interfere with host processes to optimize replication and viral pathogenesis. One of these is viral protein U (Vpu) — in vitro experiments have shown that Vpu can inhibit the nuclear factor-κB (NF-κB) signalling pathway. As the NF-κB signalling pathways that regulate innate responses in vertebrates and antimicrobial responses in Drosophila melanogaster are highly conserved, Leulier et al. investigated the function of Vpu in D. melanogaster. Overexpression of Vpu by fat-body cells specifically affected the Toll pathway and antimicrobial responses were disrupted. Because of the conservation of this pathway in flies and mammals, this indicates that Vpu might function to disrupt NF-κB-mediated innate responses.