The proinflammatory cytokine IL-32 has been linked to several chronic inflammatory conditions and has also been shown to increase during HIV or influenza infection. Zepp et al. (p. 4110) investigated the antiviral properties of IL-32 during infection with the RNA virus vesicular stomatitis virus (VSV) or the DNA virus HSV-2. WISH cells produced IL-32 in response to treatment with exogenous IL-1β or IFN-γ or with the TLR ligands polyinosine-polycytidylic [poly(I:C)] or polyuridine [poly(U)], which trigger antiviral responses. WISH cells pretreated with the γ-isoform of IL-32 were protected from subsequent VSV infection. Similarly, HSV-2 infection was reduced in Vero cells pretreated with IL-32γ, compared with untreated cells. IL-32 exerted both IFN-dependent and -independent antiviral effects, because treatment of WISH cells with soluble type I IFNR partially reduced the antiviral effect of IL-32γ treatment. Small interfering RNA-mediated silencing of IL-32 reduced the antiviral response mimicked by treatment of WISH cells with poly(I:C) or poly(U), increased the HSV-2 viral load in HUVEC cells, and quelled IFN-α production in PBMCs. In addition, the antiviral effects of IL-32 appeared to involve the PKR-eIF-2α and MxA antiviral signaling cascades. These findings better define the antiviral properties of IL-32, which may be applicable to the development of novel antiviral therapies.

Th17 cells are important in combating a variety of fungal and bacterial pathogens. Excessive Th17 responses are associated with autoimmune diseases, and the mechanisms by which Th17 responses are controlled are not completely understood. Yu et al. (p. 3946) investigated the role of T cell factor 1 (TCF-1), a transcription factor constitutively expressed in T cells, in regulating Th17 responses. TCR-mediated activation and proliferation of CD4+ T cells from mice deficient in TCF-1 were similar to levels from wild-type (WT) mice. Interestingly, naive CD4+ T cells from TCF-1 mice differentiated into Th17 cells produced significantly more IL-17, compared with WT Th17 cells. TCF-1 deletion did not cause any significant changes in cytokine signaling pathways or transcription factors that are known to affect Th17 differentiation. TCF-1 was instead found to bind directly to sites within an intron of the Il17 gene. Compared with WT mice, higher levels of IL-7Rα were expressed on the surface of Th17 cells from TCF-1–deficient mice, which could contribute to enhanced expansion and survival. TCF-1–deficient mice were also more susceptible than WT to experimental autoimmune encephalomyelitis development. Together, these results reveal that TCF-1 is involved in repressing excessive inflammatory Th17 responses, a finding that may be applied to treatment of autoimmune disorders.

Chaperones serve many functions in cells and are of particular importance for the correct folding of nascent polypeptides. Previous studies have demonstrated that tumor-specific CD8+ T cell responses are enhanced by the presence of a variety of heat shock proteins (HSPs) that function as molecular chaperones. HSPs are thought to enhance tumor-specific immunity through several mechanisms, including their ability to bind to tumor Ag peptides and facilitate cross-presentation. Tamura et al. (p. 4325) describe a role for an Hsp70 family member, binding of immunoglobulin protein (BiP), in eliciting tumor-specific CD8+ T cell responses. BiP has previously been shown to be expressed constitutively in the endoplasmic reticulum (ER) lumen and to aid in protein folding and transfer of misfolded proteins to the proteasome. Deletion of the C-terminal KDEL sequence of BiP, which is required for ER retention, followed by transfection of this modified BiP cDNA into tumor cells, resulted in continuous secretion of BiP into the culture supernatant. Injection of mice with tumor cells expressing secreted BiP resulted in very little tumor growth compared with mice injected with control tumor cells. Secreted BiP could be taken up by bone marrow-derived dendritic cells and associate with tumor-specific peptides. The BiP-chaperoned peptides could be cross-presented by dendritic cells to elicit antitumor CD8+ T cell responses, demonstrating a role for this HSP in antitumor immunity.

α B crystallin, also known as HspB5, is another molecular chaperone; it has been linked to multiple sclerosis (MS) and experimental allergic encephalomyelitis through the detection of HspB5-specific Ab and T cell responses. Discordant results among previous studies could not reconcile how HspB5 was linked to these neuroimmunological conditions. In this article, Rothbard et al. (p. 4263) show that HspB5 binds to Abs at multiple sites in a nonspecific manner. Abs from both MS patient and normal control sera bound to HspB5. Abs in these sera bound to seven other small heat shock proteins (Hsps) from the same family as HspB5. Analysis of these binding interactions by biolayer interferometry revealed that the rate of binding and degree of complex formation of Hsp5 to the nonspecific murine anti-human Fc Ab were temperature dependent. A decrease in small Hsp concentration also correlated with an increase in its rate of association with the Ab. HspB5 was able to immunoprecipitate Ig heavy and light chains from MS patient and normal sera in a nonspecific manner. Together, these observations are consistent with HspB5 behavior as a chaperone. Thus, HspB5 may not be functioning as an autoantigen, and its role, if any, during MS remains to be clarified.

β2-adrenergic receptors (β2AR) are expressed on numerous cell types, including microglia, and modulate a wide range of inflammatory responses. β2AR agonists have been developed for the management of respiratory inflammation, but their effects on neuroinflammation are not well known. Qian et al. (p. 4443) examined the impact of the long-acting β2AR agonist salmeterol on neuroinflammation in mouse models of Parkinson's disease. Salmeterol was able to significantly protect dopaminergic (DA) neurons from neurotoxicity in neuron–glia cultures exposed to LPS or the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), compared with untreated cultures. Salmeterol also protected mice treated with LPS or MPTP, each of which was used to cause Parkinson's disease-like symptoms, from significant loss of DA neurons in the substantia nigra. The neuroprotective effect of salmeterol was mediated in part by inhibition of microglial activation and production of proinflammatory molecules, as well as inhibition of MAPK and p65 NF-κB phosphorylation in microglia. These effects required β2AR expression in microglia but were exclusive of G protein-coupled receptor/cAMP signaling. Salmeterol-mediated neuroprotection did require β-arrestin2 expression, suggesting a unique mechanism by which this β2AR agonist alters inflammatory responses. These findings indicate that β2AR agonists may be a potential new class of therapeutic agents for treating neuroinflammation.

NK cells are critical to innate immune responses against viruses or tumors, and their activation state is regulated through engagement of activating and inhibitory receptors. Inhibitory receptors are also involved in NK cell licensing, during which interactions with cognate self-MHC class I molecules ready NK cells for activation. In this issue, Choi et al. (p. 3911) investigated binding interactions required for licensing via the Ly49A or Ly49C inhibitory receptors in murine NK cells. Ly49A is thought to bind to two different sites on the MHC class I ligand H2Dd to inhibit effector function. The effect of these binding interactions on licensing was tested in a transgenic mouse expressing a mutation in one of these sites (site two). Expression of this H2Dd site two mutation both prevented licensing of Ly49A+ NK cells and inhibited their natural killing activity, compared with wild-type mice. Ly49A-dependent licensing was also inhibited in transgenic mice expressing human β2-microglobulin (β2m) but deficient in murine β2m, consistent with a known role for murine β2m interactions with Ly49A at site two. Ly49C licensing was inhibited in NK cells from mice transgenic for human β2m and lacking murine β2m on the H2Db background, further supporting a role for site two during licensing. Overall, these results support roles for site two in both NK cell licensing and natural killing inhibition.

The presence of nonself surfaces such as biomaterials or transplanted tissues can set off damaging immune responses in a host and lead to negative therapeutic outcomes. The alternative pathway (AP) of complement is among the destructive responses triggered by these foreign surfaces. Wu et al. (p. 4269) sought to modulate the AP response by developing a strategy to bind factor H, a regulator of complement activation by the AP, to nonself surfaces. Factor H binding peptides were identified through the screening of two variable cysteine-constrained phage display libraries. The 5C6 peptide was of particular interest because it bound to factor H with high affinity, and this binding interaction did not interfere with either the cofactor or the regulatory activities of factor H. 5C6 peptide bound to a polystyrene surface, which recapitulates a nonself implantable biomaterial, was able to capture factor H from lepirudin-anticoagulated human plasma and inhibit the AP response. Given the pivotal role for the AP in responses against nonself surfaces, these data identify a peptide that can be developed into a therapeutic intervention for controlling destructive complement activation.

Allergic responses in individuals suffering from asthma cause airway infiltration by a variety of immune cells, which can lead to inflammation and airway obstruction. The role of anti-inflammatory molecules in modulating allergic asthma is not well understood. Marino et al. (p. 4433) assessed the role of secretory leukocyte protease inhibitor (SLPI), a serine protease expressed in mucosal tissues, during allergic asthma. SLPI transgenic mice were used to study the effect of SLPI overexpression in an OVA model of allergic asthma. OVA-sensitized SLPI transgenic mice showed significantly lower airway resistance, plasma IgE, and eosinophilic infiltration upon OVA challenge, compared with wild-type mice. SLPI overexpression also protected mice from significant goblet cell hyperplasia. OVA challenge of sensitized SLPI knockout mice caused more severe asthma symptoms, compared with wild-type mice, including higher airway resistance and plasma IgE, as well as greater eosinophilia and goblet cell hyperplasia. Treatment with resiquimod, a TLR7/8 agonist that has been shown to protect against asthma, significantly reduced allergic asthma inflammatory responses independent of SLPI expression, which may be due to its ability to modulate NF-κB signaling. The use of these unique mouse models supports independent roles for SLPI and resiquimod in modulating allergic asthma, which may lead to improved asthma treatments in the future.

Summaries written by Christiana N. Fogg, Ph.D.