High-density lipoproteins have important anti-inflammatory and atheroprotective properties, and mimetic peptides of their major structural component, apolipoprotein A-I (apoA-I), are being researched in the treatment of cardiovascular diseases. Yao et al. (p. 576) hypothesized that the anti-inflammatory capacities of apoA-I mimetic peptides could be effective in asthma treatment and therefore investigated one such peptide, designated 5A, in a mouse model of house dust mite-induced asthma. Systemic administration of the 5A apoA-I mimetic peptide prior to asthma induction effectively inhibited airway inflammation, hyperreactivity, and remodeling, whereas a control peptide had no effect. Analysis of the mechanism responsible for disease amelioration indicated that the 5A peptide inhibited the production of Th2 and Th17 cytokines and of CC chemokines that induce infiltration of the lung by eosinophils, basophils, and T cells. The 5A apoA-I mimetic peptide also inhibited alternative macrophage activation but did not affect serum IgE levels. Taken together, these data suggest that apoA-I mimetic peptides like 5A could represent a novel therapeutic strategy for patients with severe asthma that does not respond to standard treatment.

Following hematopoietic stem cell transplantation, graft-versus-host disease (GVHD) can develop when donor T cells primed by recipient APCs attack allogeneic host tissues. Effective adaptive immune responses to pathogens require APC activation via pattern recognition receptor (PRR) signaling, but the importance of APC activation in GVHD is not clear. To address this issue, Li et al. (p. 230) analyzed GVHD development in recipient mice whose hematopoietic cells were deficient in various pathways of APC activation. Recipient mice lacking either TLR4 or CD40 developed GVHD at levels comparable to those in wild-type recipients, suggesting that APC activation via these pathways was not important in this disease model. To more broadly address PRR-mediated APC activation, bone marrow chimeras were developed with hematopoietic cells deficient in MyD88, TRIF, or both MyD88 and TRIF. Intact GVHD developed when these chimeric mice were used as transplant recipients, which confirmed that disease development did not require signaling through TLRs or IL-1β. Th1 polarization of donor CD4+ T cells was also intact in all of these mice and did not require host APC-derived IL-12. GVHD also developed similarly to that in wild-type recipients in mice lacking the IFN-α receptor, B7.1 + B7.2, or IL-12, further supporting the irrelevance of APC activation in these disease models. Thus, T cell activation in GVHD may differ fundamentally from that involved in responses to pathogens.

Class switch recombination (CSR) in B cells is preceded by germline transcription and results in the selection of a C region whose functional characteristics direct the ensuing immune response. The germline H chain transcripts are initiated at intervening (I) exons and have cytokine-responsive promoter regions that are proposed to be responsible for specific cytokine-driven CSR. To directly investigate this idea, Dunnick et al. (p. 350) developed mice carrying a transgenic H chain C region locus in which the promoter regions and I exons for Cγ1 and Cγ2a were swapped. These mice produced chimeric Iγ1Cγ2a and Iγ2aCγ1 germline transcripts under the control of their new promoter/I exon regions. If cytokine-driven CSR was indeed controlled by these regions, then recombination to Cγ1 should be directed by IFN-γ rather than IL-4, and recombination to Cγ2a should be directed by IL-4 instead of IFN-γ in these mice. Indeed, B cell activation in the presence of IL-4 induced CSR to Cγ2a and consequent secretion of IgG2a, whereas activation in the presence of IFN-γ induced CSR to Cγ1, albeit at a low level. This transgenic system characterizes the relative strength of the Cγ1 and Cγ2a promoter and I exon regions and indicates that these regions regulate the cytokine regulation of CSR, but are not the only factors that control its magnitude.

Glucocorticosteroids (GCSs) are immunosuppressive drugs whose specific mechanisms of action are incompletely characterized. To study the modulation of the cutaneous immune response by GCSs, Stary et al. (p. 103) investigated oral GCS treatment of patients with nickel allergy. GCS-induced reductions in skin inflammation were associated with a decreased leukocytic infiltrate and increased numbers of epidermal Langerhans cells (LCs) and dermal regulatory T cells (Tregs) in epicutaneous lesions. Following GCS treatment, skin lesions also demonstrated a dramatic upregulation of TGF-β, as well as increased levels of RANK and RANKL. In vitro, GCS-treated LCs showed an immature phenotype, and these LCs, but not other dendritic cell subsets, promoted the proliferation and suppressive activity of Foxp3+ Tregs. GCS administration induced LCs to produce TGF-β, which was required for their stimulation of Tregs. Further, RANK and RANKL were directly upregulated on LCs and keratinocytes, respectively, by GCSs. This demonstration that systemic GCS treatment of patients with contact allergy can impart Treg-enhancing functions to LCs will be useful for investigations of GCS activity and therapeutic potential, especially in cutaneous immunity.

Exosomes are endosome-derived membrane vesicles that can be released from a variety of cell types and have been implicated in lymphocyte stimulation, inhibition, and tolerance. To address mechanisms of exosome action, Vallhov et al. (p. 73) examined the interactions of exosomes derived from different cell types with cells in human peripheral blood. Exosomes from breast milk, which have been reported to be tolerogenic, and from dendritic cells, which have been reported to be stimulatory, preferentially targeted monocytes and were internalized. In contrast, “repressive” exosomes produced by an EBV-transformed B cell line targeted B cells and remained associated with their cell surface. This exosome–B cell interaction required expression of CD21 on the B cells and the EBV glycoprotein gp350 on the exosomes. EBV virions were not present in the exosome preparations, confirming that the interaction observed involved exosomes and not viral infection. Finally, incubation of B cells with these exosomes inhibited subsequent EBV infection. These data identify a protective interaction between virally infected B cell-derived exosomes and uninfected B cells and suggest that exosomes expressing gp350 could be used to specifically target B cells in vaccines.

Long-term protection against influenza infection requires the establishment of a long-lived pool of memory CD8+ T cells able to respond to conserved viral epitopes. Verbist et al. (p. 174) analyzed the effects of localized production of IL-15 on the lung CD8+ effector T cell (Teff) pool in hopes of enhancing anti-influenza immunity. Influenza infection induced IL-15 expression in the lung, and mice deficient in IL-15 demonstrated an airway-specific reduction of Ag-specific CD8+ Teffs compared with control mice. These Teffs were restored to wild-type levels upon intranasal treatment with exogenous IL-15/IL-15Rα complexes (IL-15c). In wild-type infected mice, treatment with IL-15c induced migration of influenza-specific CD8+ Teffs into the lung airways. This recruitment of CD8+ Teffs, most likely from the circulation, was directly mediated by IL-15c and not by IL-15’s effects on chemokine production. Intranasal administration of IL-15c to mice 10–20 d postinfection led to a quantitatively and qualitatively enhanced pool of CD8+ memory T cells in the lung, establishing therapeutic relevance of these data. This identification of a role for IL-15c in CD8+ Teff migration to the site of influenza infection and consequent enhanced memory development suggests that this cytokine complex could serve as a useful vaccine adjuvant to prolong anti-influenza immunity.

The adaptor protein TRAF3 mediates signaling through TLRs and TNFR superfamily members and plays an important homeostatic role in B cell apoptosis. However, the involvement of TRAF3 in T cell function is less clear. Xie et al. (p. 143) generated mice specifically lacking TRAF3 in T cells (T-TRAF3−/−) and found that TRAF3 deficiency led to an increased frequency of regulatory T cells, but did not generally affect T cell development or homeostasis. However, compared with controls, T-TRAF3−/− mice demonstrated defective T-dependent IgG1 responses and delayed Ag-specific T cell expansion and migration following infection with Listeria monocytogenes. In vitro, TRAF3 deficiency impaired proliferation, survival, and effector cytokine production of both CD4+ and CD8+ T cells in response to stimulation through CD3 and CD28. These defects were associated with impaired phosphorylation of CD3/CD28 receptor-proximal signaling components following TCR + CD28 stimulation but not TCR stimulation alone. Immunoprecipitation experiments suggested a mechanism for TRAF3 activity by identifying this molecule as a component of the TCR/CD28 signaling complex. Thus, TRAF3 is an important player in T cell activation, a function quite distinct from its proapoptotic role in B cells.

In the resting lung, alveolar macrophages (AMs) have a suppressive phenotype that keeps inflammatory responses in check. Following infection, neutrophils are recruited into the lung and de-repress AMs through a mechanism requiring cell–cell contact. IL-1R–associated kinase-M (IRAK-M) is a regulatory molecule expressed in resting AMs that blocks TLR activation and is cleaved upon AM contact with neutrophil membranes. To analyze the potential involvement of IRAK-M in AM–neutrophil interactions and inflammatory regulation, Kobayashi et al. (p. 403) compared the AMs of pneumonia patients with those of healthy controls. The AMs of the pneumonia patients expressed truncated IRAK-M, whereas those of healthy individuals expressed only the full-length version, suggesting IRAK-M cleavage during infection. Indeed, AM contact with neutrophils or their membranes did not alter IRAK-M expression but did lead to its cleavage and release from the cell membrane. Caspase-6 (CASP-6) was found to associate with IRAK-M in resting AMs and cleave IRAK-M upon neutrophil contact. Supporting the functional relevance of this CASP-6–mediated cleavage, macrophages expressing a cleavage-resistant IRAK-M mutant or CASP-6–targeted small interfering RNA demonstrated impaired TNF-α production following neutrophil contact. In a model of sepsis, CASP-6–deficient mice demonstrated decreased TNF-α production and increased survival compared with wild-type mice. These data present a mechanism by which lung-infiltrating neutrophils activate AMs and identify CASP-6 as a regulator of innate immunity.

Summaries written by Jennifer Hartt Meyers, Ph.D.