Presently, few mouse models exist to study the chronic skin disorder atopic dermatitis (AD). In this issue, Matsushima et al. (p. 2340) characterize a novel spontaneous murine model of AD and identify the causative underlying recessive mutation. Affected KOR-adjm/adjm (AD from Japanese mice) animals exhibited AD-like symptoms mainly localized to the face and ears. Similar to human AD, the epidermal layer of affected skin of KOR-adjm/adjm mice was thickened and infiltrated with inflammatory cells, including eosinophils. Affected mice exhibited elevated levels of serum IgE, which increased with age. Additionally, a sexual disparity in levels of IgE was observed, as serum IgE levels in young female mice were two times higher than their male counterparts. Linkage analysis identified a single locus on mouse chromosome 10 that contained the gene encoding TNFR-associated factor 3 interacting protein 2 (Traf3ip2), the mouse homolog to human CIKS/Act1. Affected mice had a single point mutation in the second exon of the Traf3ip2 gene that resulted in a C-terminal truncated protein. Traf3ip2 has previously been shown to function as an adaptor protein in IL-17–mediated signaling pathways. Interestingly, IL-17 was found to be highly expressed in the serum of affected female mice, and severely affected homozygous female mice had increased levels of Th17 cells in their spleens compared with unaffected female mice. Taken together, these data ascribe a role for Traf3ip2 protein in the development of AD.

Akin to CD4+ T cells, CD8+ T cells can acquire IL-17–secreting or IFN-γ–secreting phenotypes, respectively termed Tc17 and Tc1 cells. Previous studies found that Tc17 cells can mediate immunity to viral infection, but the mechanism is unclear, as cytotoxic activity appeared to correlate with a switch to a Tc1 phenotype. To better understand the role of Tc17 cells in viral clearance, Yeh et al. (p. 2089) studied Tc17 cells in vitro and employed a vaccinia virus infection model. In vitro-derived Tc17 cells required TGF-β and IL-6 to maintain IL-17 expression and would largely convert to the Tc1 phenotype in response to IFN-γ or IL-12 treatment. However, adoptively transferred Ifng−/− Tc17 cells were resistant to conversion in vivo and still mediated viral clearance. Furthermore, virus-specific Tc17 cells isolated post viral infection exhibited cytotoxic activity. The Tc17 cytotoxicity was determined to be mediated, at least partially, by Fas ligand but not granzyme B. These data reveal that Tc17 cells can exhibit antiviral cytotoxic activity without requiring conversion to the Tc1 phenotype.

Administration of α-galactosylceramide, the specific agonist of invariant NKT (iNKT) cells, during the induction phase of experimental autoimmune encephalomyelitis prevents disease onset. To gain insights into this finding, Monteiro et al. (p. 2157) evaluated iNKT cells following α-galactosylceramide administration. In treated mice that showed protection from experimental autoimmune encephalomyelitis, a population of iNKT cells expressing Foxp3 was discovered in the draining cervical lymph nodes. These Foxp3+ iNKT cells were not detectable in lymphoid organs of naive mice and displayed phenotypic characteristics of both induced T regulatory cells (iTregs) and NKT cells. In keeping with NKT cells, Foxp3+ iNKT cells expressed promyelocytic leukemia zinc finger protein and exhibited preferential homing to the liver following adoptive transfer. Like conventional CD4+ T cells, iNKT cells expressed Foxp3 when activated in the presence of TGF-β. Accordingly, activation of iNKT cells in the TGF-β–rich environment of the gut mucosa resulted in the accumulation of Foxp3+ iNKT cells in the mesenteric lymph nodes. Analogous to Tregs, Foxp3+ iNKT cells suppressed CD4+CD25 responder cell proliferation via a contact-dependent, GITR-mediated mechanism. These findings demonstrate that iNKT cells can acquire suppressive functions similar to those of Foxp3+ Treg cells.

The bony fish, or Osteichthyes, are the largest class of vertebrates and include seemingly disparate fish, such as carp and sea horses. The MHC loci of various bony fish species have been identified and sequenced, but presently there is little functional knowledge. In this issue, Chen et al. (p. 2209) used a grass carp (Ctenopharyngodon idella) fosmid library to identify two MHC class I (Ctid-UBA) genes, designated UBA*0101 and UBA*0201, which appeared to be alleles based on genomic organization. A high level of polymorphism in the gene, as well as universal tissue expression, indicated that Ctid-UBA was a classical class I gene. Ctid-UBA protein, refolded with grass carp β2-microglobulin, bound the grass carp hemorrhagic virus antigenic peptide P1. Three-dimensional structural analysis of this trimer indicated that the α1 and α2 domains formed the Ag-binding groove. A Ctid-UBA*0102/P1 Ag tetramer stained P1 Ag-immunized grass carp spleen cells, indicating that grass carp could mount a Ctid-UBA–restricted CTL response. Finally, analyses of the Ctid-UBA promoter region revealed an IFN-stimulated regulatory element sequence. Correspondingly, the injection of grass carp with grass carp rIFN-α significantly increased Ctid-UBA expression compared with PBS-injected controls. These findings significantly further our understanding of bony fish MHC class I-restricted Ag presentation and its regulation.

The proinflammatory cytokine IL-1β is a key player in the pathology of the chronic autoimmune diease rheumatoid arthritis (RA). Activated macrophages are a significant source of IL-1β following stimulation of the purinergic P2CX7 receptor (P2X7R) by extracellular ATP, which is released by damaged tissues. Studies of the role of P2X7R signaling in RA have largely focused on the connection between activated macrophages and P2X7R-mediated release of IL-1β. Lopez-Castejon et al. (p. 2611) investigated the functional role of P2X7R on resting bone marrow-derived macrophages (BMDMs) and found that ATP-mediated stimulation of P2X7R also induced the release of cathepsins, which are lysosomal proteases that have been implicated in RA-associated joint damage. Unlike IL-1β, cathepsin secretion was only partially sensitive to calcium depletion and unaltered by high potassium levels, indicating that P2X7R-induced release of cathepsin and IL-1β occur through different pathways. In unstimulated wild-type BMDM supernatants, constitutive gelatinolytic activity was observed and increased significantly in response to ATP stimulation. In contrast, supernatants from P2X7R−/− BMDMs exhibited reduced constitutive gelatinolytic activity, and ATP stimulation had no effect. These data reveal an IL-1β–independent mechanism for P2X7R-mediated tissue damage.

Respiratory syncytial virus (RSV) is a negative strand ssRNA virus. As such, it is recognized by TLR7/8. When Lukacs et al. (p. 2231) infected TLR7−/− mice with RSV, viral titers and viral gene expression were not significantly changed compared with wild-type mice; however, a more severe lung pathology was observed, characterized by increased inflammation and mucus production. Correspondingly, there were greater numbers of goblet cells and increased expression of the mucus-associated genes Muc5ac and Gob5. Increased numbers of inflammatory cells were not observed nor were there alterations in type I IFN expression. Instead, the modified RSV response appeared to correlate with the elevated expression of the mucogenic cytokines IL-4, IL-13 and, more predominantly, IL-17A. In vitro, RSV infection of TLR7-deficient bone marrow-derived dendritic cells (DCs) induced increased expression of the Th17-promoting cytokine IL-23 compared with wild-type DCs. This was also observed in the lungs of RSV-infected TLR7−/− mice. When RSV-infected mice were passively immunized with IL-17–neutralizing Ab, RSV-infected TLR7−/− mice exhibited decreased mucus production compared with control IgG-treated mice, as well as decreased expression of Muc5ac and Gob5 genes, without affecting the expression of IL-4 and IL-13. Collectively, these data suggest that TLR7 deficiency skews DCs to induce increased levels of IL-17 expression, which in part mediates the altered pathology observed in RSV-infected TLR7−/− mice.

The proinflammatory cytokine IL-1β, an important mediator of sepsis and septic shock, is released by activated macrophages and neutrophils. A key regulator of IL-1β activity is the IL-1R antagonist (IL-1Ra), which is largely produced by myeloid cells and hepatocytes and competitively binds to IL-1R without inducing intracellular signaling events. IL-1Ra–deficient mice are highly susceptible to LPS-induced lethality, but the relative contributions of hepatocyte-and myeloid cell-derived IL-1Ra expression are not known. To better define the biological role of IL-1Ra during endotoxemia and sterile inflammation, Lamacchia et al. (p. 2516) created hepatocyte- and myeloid cell-specific IL-1Ra singly deficient mice, IL-1RaΔH and IL-1RaΔM, respectively, and IL-1Ra doubly deficient mice, IL-1RaΔH+M. In response to LPS, myeloid cells were the greatest source of LPS-induced IL-1Ra derived from liver, spleen, and lung. Furthermore, compared with IL-1Ra−/− mice, IL-1RΔH mice, but neither IL-1RaΔM nor IL-1RaΔH+M mice, exhibited significantly improved survival from LPS-induced systemic inflammation. In contrast, hepatocytes were found to be the largest source of IL-1Ra in response to IL-1β–induced sterile inflammation. These data define distinct roles for myeloid cells and hepatocytes as sources of IL-1Ra in response to LPS- and IL-1β–induced systemic inflammatory responses.

CD30 ligand (CD30L), a membrane-associated glycoprotein belonging to the TNF superfamily, and its receptor CD30 are expressed by activated CD4+ T cells. Engagement of these molecules induces bidirectional signaling pathways. Under Th17-polarizing conditions, Sun et al. (p. 2222) found that cultured CD4+CD62LhighCD44low naive CD30L−/− and CD30−/− T cells exhibited an impaired ability to differentiate into Th17 cells and produced increased levels of IL-2 compared with wild-type (WT) cells. Neutralization of IL-2 partially restored IL-17A production levels and increased CD30L−/− and CD30−/− Th17 cell numbers. Both CD30L and CD30 pathways were found to induce Th17 differentiation, whereas only CD30L reverse signaling inhibited IL-2 production. In vivo, the T cells of CD30L-deficient mice secreted higher levels of IL-2 and displayed a decreased propensity to develop into Th17 cells compared with WT mice. Finally, when CD30L−/− or WT recipient mice received CD4+CD45RBhigh WT T cells, the mice developed colitis and signs of wasting, whereas these symptoms were attenuated in WT SCID recipient mice receiving CD30L−/− T cells. These data revealed that reciprocal engagement of CD30L/CD30 on T cells plays a positive role in regulating Th17 differentiation.

Summaries written by Meredith G. Safford, Ph.D.