Disruptions in T and B cell immunity have long been known to be vital to the development of systemic lupus erythematosus (SLE). However, the roles of innate immune abnormalities in SLE pathogenesis are less thoroughly understood. Denny et al. (p. 3284) sought to define the function of an abnormal subset of neutrophils found in the circulation of SLE patients, referred to as low-density granulocytes (LDGs). These LDGs had an activated yet somewhat immature phenotype, and SLE patients with high frequencies of LDGs demonstrated clinical features, including skin manifestations and synovitis, that were not observed in patients with lower frequencies. Compared with autologous normal-density neutrophils from SLE patients and control neutrophils from healthy subjects, LDGs demonstrated reduced phagocytic capacity and increased production of proinflammatory cytokines and type I IFNs. The authors addressed the potential role of LDGs in the imbalance between vascular damage and repair observed in SLE patients and determined that LDGs mediated marked cytotoxic effects on endothelial cells. Type I IFN production by LDGs also impaired endothelial cell maturation in proangiogenic cultures, indicating that LDGs could inhibit vascular repair. Taken together, these data define LDGs as an important pathogenic cell type in lupus patients and provide insight into neutrophil involvement in SLE progression.

Sexually transmitted infections, such as gonorrhea, caused by Neisseria gonorrhoeae (gonococcus [GC]), increase the likelihood of HIV-1 transmission, but the mechanisms by which viral susceptibility is enhanced have not been fully elucidated. To address this issue, Ding et al. (p. 2814) analyzed the effects of GC exposure on HIV infection of primary CD4+ T cells. GC enhanced HIV replication in resting, but not activated, primary CD4+ T cells without altering T cell proliferation. This GC-induced augmentation of HIV infection was mediated by TLR2 activation and required IL-2 signaling. Treatment of CD4+ T cells with GC or TLR2 agonists induced the upregulation of T cell activation markers and HIV coreceptors, all of which would be expected to enhance HIV infectivity. Kinetic analysis determined that the effects of GC or TLR2 agonists were most pronounced at the step of nuclear import, after viral entry and reverse transcription. These data define a mechanism by which a common sexually transmitted infection can directly enhance HIV infection of resting CD4+ T cells and have implications for the development of strategies to prevent HIV transmission.

The life span of double-positive (DP) thymocytes determines the extent to which receptor editing can occur. Regulation of DP cell survival therefore affects the composition of the mature T cell repertoire. Activity of the c-Myb transcription factor, which is encoded by the Myb proto-oncogene, is vital to the proper progression of thymocyte differentiation. Through the analysis of a conditional Myb knockout mouse, Yuan et al. (p. 2793) sought to clarify the mechanism by which c-Myb might modulate DP thymocyte survival. Myb mRNA expression was found at high levels in small preselection DP cells, and c-Myb protected these cells from apoptosis mediated via the intrinsic pathway. In the absence of c-Myb, receptor editing was impaired, and expression of the survival factor Bcl-xL was significantly reduced. This indicated that c-Myb–induced Bcl-xL prolonged the survival window in small preselection DP thymocytes, thus allowing them to incorporate distal Jα gene segments into their TCRs. c-Myb was further found to regulate transcription of the gene encoding Bcl-xL through a mechanism independent of two transcription factors known to regulate DP thymocyte survival, TCF-1 and RORγt. These data describe a new role for c-Myb in thymocyte development and add significantly to our knowledge of the processes controlling DP thymocyte survival and, thus, repertoire diversity.

MHC class I (MHC-I) molecules present spe-cific peptides of 8–9 aa, whose composition is generally determined by the structure of the MHC-I peptide-binding groove. However, the mechanisms by which optimal peptides are generated are relatively unclear, leading Blanchard et al. (p. 3033) to analyze the peptides presented by MHC-I molecules in mice lacking the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP). Mass spectrometric analysis of peptides bound to MHC-I molecules in ERAAP−/− mice versus wild-type mice revealed longer peptides bound to MHC-I in the absence of ERAAP. The authors next addressed the effects of ERAAP deficiency on Ag presentation during infection with mouse CMV. Antiviral CD8+ T cell responses were altered both qualitatively and quantitatively in the absence of ERAAP, reflecting recognition of an altered repertoire of MHC:peptide ligands. Infection of ERAAP−/− mice led to the preferential expansion of CD8+ T cells recognizing a 10-aa peptide that was an N-terminally extended version of an immunodominant 9-aa peptide recognized by CD8+ T cells in wild-type mice. These data demonstrate the essential role of ERAAP in determining the length and repertoire of peptides presented by MHC-I.

Effective antiviral responses involve complex host-virus interactions that require extensive modulation of host gene expression. To define transcriptional regulatory networks responsible for the establishment of the antiviral state in dendritic cells (DCs), Zaslavsky et al. (p. 2908) developed a novel approach to integrate time-dependent promoter analysis with the more static view of gene transcription obtained through genome-wide expression profiling. Infection of human monocyte-derived DCs with Newcastle disease virus was chosen as a model because of the inability of this virus to evade the IFN response, which allowed the authors to analyze the progression of an uninhibited antiviral response. It was found that the immune response to Newcastle disease virus infection could be represented by a single convergent regulatory network consisting of several distinct temporal phases driven by a stepwise cascade of transcription factor activity. The transcription factors involved in this cascade included several not previously implicated in antiviral immunity, including ALX1, FOXC1, and RUNX3. These data not only provide a framework that will be useful to future studies of antiviral responses and immune subversion by viral infection but also introduce a novel methodology that may be applied to modeling the genetic programs that underlie other types of cell state transitions.

The genes encoding the closely related cytokines IL-3 and GM-CSF are induced by the same signaling pathways, but the epigenetic modifications involved in the regulation of the IL-3/GM-CSF locus in T cells are not well understood. Mirabella et al. (p. 3043) developed a transgenic mouse model containing the human IL-3/GM-CSF locus and performed comprehensive studies of the fate of this locus during T cell development and differentiation. In double-positive cells in the thymus, the IL-3/GM-CSF locus was transcriptionally silent but did not appear to be repressed by histone modifications or DNA methylation. Maximal expression of the locus was observed in mature activated T cells and was accompanied by extensive histone acetylation and methylation. The activation of these genes was associated with the transcription of noncoding RNAs initiated within the enhancer elements of the locus, which may have been responsible for at least some of the chromatin modifications. The IL-3 gene, but not the GM-CSF gene, was also found to be preferentially expressed in Th2 versus Th1 cells. Interestingly, the authors found that human memory CD4+ T cells maintained the modified chromatin structure of activated T cells, suggesting a basis for the ability of memory cells to rapidly respond to stimulation.

A great deal of knowledge regarding viral pathogenesis has been gleaned from the identification of genes involved in susceptibility to viral infection. Susceptibility to mouse adenovirus type 1 (MAV-1), which bears similarities to human adenoviruses, varies greatly between mouse strains and has been mapped to a quantitative trait locus on mouse chromosome 15, Msq1. Through analysis of 1396 mice produced by backcrossing susceptible SJL/J mice to resistant BALB/cJ mice, Spindler et al. (p. 3055) reduced the 18-Mb interval to which Msq1 had previously been mapped to 0.75 Mb that encompassed 14 lymphocyte Ag 6 (Ly6) and Ly6-related genes. Haplotype analysis of the Ly6 complex demonstrated that mouse strains with the Ly6.2 lymphocyte specificity were more likely to be susceptible to MAV-1 infection, whereas Ly6.1 mouse strains were generally resistant. Several inbred mouse strains previously uncharacterized with regard to MAV-1 susceptibility were analyzed, and 129S6, PL/J, and FVB/NJ mice were found to be susceptible. Through analysis of mice obtained by backcrossing (129S6 × BALB/cJ)F1 progeny to BALB/cJ mice, Msq1 was mapped to the same 0.75-Mb region of chromosome 15 in 129S6 mice as that identified in SJL/J mice. This study suggests that members of the Ly6 family, which are largely uncharacterized functionally, have important antiviral activities.

Vascular adhesion protein-1 (VAP-1) is an amine oxidase expressed on endothelial cells that is proposed to enhance leukocyte extravasation through both adhesive and enzymatic functions. VAP-1–deficient mice demonstrate delayed tumor progression, but the mechanism of VAP-1 action in tumor development is unclear. Marttila-Ichihara et al. (p. 3164) therefore assessed the effects of anti–VAP-1 Abs and VAP-1 enzymatic inhibitors in several tumor models. Anti–VAP-1 Abs inhibited the recruitment of CD8+ T cells into tumors but did not affect the recruitment of myeloid cells, nor did they alter tumor neovascularization or progression. In contrast, inhibitors of VAP-1 oxidase activity significantly diminished the intratumoral accumulation of Gr-1+CD11b+ myeloid cells and impaired tumor progression and neoangiogenesis. Neither method of VAP-1 inhibition affected the recruitment of regulatory T cells or type 2 macrophages, however. The observation that small molecule enzymatic inhibitors of VAP-1 selectively reduced infiltration of myeloid-derived suppressor cells into tumors and consequently slowed tumor progression suggests that these molecules may boost the effectiveness of cancer treatment.

Summaries written by Jennifer Hartt Meyers, Ph.D.