The cover shows a histological analysis of an ear section from a C57BL/6 mouse that was first sensitised with 2,4-dinitrofluorobenzene on the belly and then challenged 4 days later with 2,4-dinitrofluorobenzene on the ear. Haematoxylin and eosin staining shows massive skin infiltration by mononuclear cells and granulocytes 24 h after challenge. The image is from Rouzaire et al. (pp. 80–88) in which the authors show that NK cells and T cells induce different types of inflammatory reactions in the skin during recall responses to haptens; of note, NK cell-mediated pathogenesis does not rely on cellular infiltrate.
A ‘ménage à trois’ in the germinal centre involving human γδ T cells
Vγ9/Vδ2 T cells comprise a minor subset of unconventional T cells in the blood which uniquely respond to HMB-PP, a non-peptide metabolite produced by a large range of microbial pathogens. For reasons that are not understood Vγ9/Vδ2 T cells and immune responsiveness to HMB-PP are found only in higher primates and are absent in all other vertebrates including mice. In this issue, Bansal et al. demonstrate that HMB-PP induces upregulation of the IL-21 receptor on human Vγ9/Vδ2 T cells. The authors show that IL-21 plays a co-stimulatory role in the induction of CXCL13, CXCR5 and ICOS expression by HMB-PP-activated Vγ9/Vδ2 T cells and in the potential of these cells to provide B-cell help. These findings suggest that the ‘ménage à trois’ of Vγ9/Vδ2 T cells, TFH cells and B cells in the germinal centres of secondary lymphoid tissues is likely to impact on the generation of high-affinity, class-switched antibodies in microbial infections.
The heart of HIV-associated tuberculosis
Compared with those not infected with HIV, HIV-infected individuals are up to 30 times more likely to develop tuberculosis, with an increased risk of extrapulmonary disease. In this issue, Matthews et al. show that in the pericardial form of extrapulmonary tuberculosis, increased HIV replication at the tuberculous disease site leads to the elimination of the CCR5+ effector memory CD4+ T-cell population by the virus. This elimination of the memory population is accompanied by the recruitment of less differentiated cells to the disease site. The presence of polyfunctional CD4+ T cells expressing TNF, IL-2 and IFN-γ is consistent with the less mature phenotype of CD4+ memory T cells at the disease site of HIV-1-infected patients. Interestingly, and unlike other extrapulmonary tuberculous disease sites, there are instances where the compartmentalisation of antigen-specific T cells is not detectable. As this lack of compartmentalisation might limit diagnostic application in pericardial tuberculosis, the underlying reasons require further elucidation.
Hybrids, not just for cars: γδ T-cell transcriptome is a hybrid of αβ T-cell and NK-cell signatures
Human γδ T cells reactive to non-peptide phosphoantigens represent promising new anti-cancer immunotherapeutics, but they are hitherto poorly characterized. In this issue, Pont et al. perform the first Affymetrix-based transcriptome analysis of human phosphoantigen-specific γδ T cells in resting and activated conditions. In comparison with a broad collection of transcriptomes from both healthy lymphocytes and lymphoma cells, phosphoantigen-specific γδ T cells are found to cluster with – and between – healthy αβ T and NK cells. γδ T cells show gene expression signatures corresponding to both αβ Th1 and NK cell functional activities, but not to phagocytic or antigen-presenting cell (APC) bioactivities. Functional studies show that Th1 cytokine, chemokine and cytotoxic activities reflect a high mitotic activity at later time points rather than antigen-presenting functions. The transcriptomes from these phosphoantigen-specific γδ T cells are therefore strikingly distinct from that of NK/T or peripheral T-cell lymphomas of the γδ subtype.
Natural antibody-producing B-1 cells exist in the bone marrow
A small subset of B cells, B-1 cells, is thought to generate “natural antibodies” (nAbs) – antibodies that are generated without overt immunization and importantly contribute to antimicrobial defenses and tissue homeostasis. However, while nAb production occurs mainly in the spleen and bone marrow (BM), B-1 cells are most prominent in the body cavity of mice and are not thought to exist in BM. In this issue, Choi et al. resolve this apparent conundrum by identifying, for the first time, nAb-secreting B-1 cells in the BM. BM B-1 cells share many characteristics with splenic B-1 cells, but are distinct from their counterparts in body cavities, which despite their relative abundance contribute little to the nAb pools. nAb-producing B-1 cells are also distinct from conventional plasma cells. These data highlight the significant contribution of BM B-1 cells as nAb-producers and supports the view that body cavity B-1 cells function as rapidly inducible cellular reservoirs, but not pools, of nAb-producing cells.
From our sister journals – Come on in! How antibodies can also act inside cells
It was recently discovered that – besides providing extracellular protection against pathogens – antibodies bound to adenovirus can also enter the cell and lead to the disposal of the virus intracellularly. McEwan et al. describe how this antibody-dependent intracellular neutralisation (ADIN) works: inside the cell the antibodies are recognized by the receptor TRIM21, which binds to IgG with high affinity. The binding of TRIM21 to IgG subsequently recruits the ubiquitin-proteasome system, leading to the degradation of the virus. Furthermore the authors discuss how this discovery alters our view of the way in which antibodies neutralize viral infection and what implications this may have for future research.