Mice lacking the gene encoding the IL-1R antagonist (Il1rn−/−) develop spontaneous arthritis, aoritis, and a skin disease that resembles psoriasis. Although the arthritis and aoritis appear to be mediated via T cell-driven autoimmunity, the pathogenesis of the inflammatory skin disease is not fully understood. Nakajima et al. (p. 1887) analyzed the involvement of proinflammatory cytokines in skin inflammation in these mice in hopes of clarifying the mechanisms of disease. The expression of several inflammatory cytokines and chemokines was upregulated in the inflamed skin of Il1rn−/− mice. Of these cytokines, TNF, but not IL-6, was required for skin inflammation. Although it is important for arthritis and aoritis in Il1rn−/− mice, IL-17 was dispensable for dermatitis development. Interestingly, T cells were not involved in skin inflammation. Instead, inflammation required skin-resident cells, likely TNF-producing keratinocytes. Thus, psoriasis-like disease in these mice appears to be caused by the actions of excess IL-1 signaling on keratinocytes in the absence of T cell-mediated autoimmunity. This mouse model will allow investigation of the possibility that some skin inflammation in human psoriasis may be caused without autoimmune involvement.

In a subset of HIV-infected individuals undergoing antiretroviral therapy (ART), viral replication is successfully suppressed without significant CD4+ T cell regeneration. Treatment with IL-7, which plays an important role in the maintenance of T cell levels, may help restore CD4+ T cells following ART. Using SIV-infected, ART-treated macaques, Leone et al. (p. 1650) investigated the usefulness and mechanisms of different dosing strategies of glycosylated recombinant simian IL-7 (rsIL-7gly) in T cell recovery. Administration of rsIL-7gly transiently increased proliferation of naive and memory CD4+ and CD8+ T cells without increasing viral replication. The authors determined an optimal spacing of doses to increase T cell proliferation but did not observe a sustained increase in peripheral T cell numbers. However, treatment with more frequent, clustered doses of rsIL-7gly increased levels of CD4+ and CD8+ T cells in the peripheral blood for the duration of the 112-d study. This strategy particularly enhanced levels of central memory CD4+ T cells, which are crucial to long-term T cell repopulation. These sustained increases in T cell numbers were traced to initial increases in T cell proliferation followed by enhanced cell survival, compared with T cells in macaques treated with ART alone. This optimization of IL-7 treatment in the SIV model may provide new strategies for the treatment of HIV-infected patients.

Stimulation of the costimulatory molecule 4-1BB has strong anticancer effects that appear to be more complicated than simple enhancement of T cell activation. Upon investigating the effects of 4-1BB on CD8+ T cell-sensitive tumors, Choi et al. (p. 1404) found that 4-1BB/ mice were surprisingly resistant to tumor growth. Comparison of wild-type and 4-1BB/ mice showed that CD8+ T cells were the main antitumor effectors following 4-1BB stimulation in the former, whereas both CD8+ T cells and NK cells were required for tumor suppression in the latter. Although NK cells were severely depleted in the bone marrow of wild-type mice upon 4-1BB triggering, they were expanded in 4-1BB/ mice during tumor growth. 4-1BB signaling in the periphery was found to block NK cell development in the bone marrow by inducing the production of large amounts of IFN-γ from T cells and NK cells. These data may have important implications for tumor therapies involving stimulation of 4-1BB and suggest that during the course of tumor progression, host immunity shifts from innate responses mediated by NK cells to adaptive responses mediated by CD8+ T cells through the actions of 4-1BB–induced IFN-γ.

There is no effective vaccine for Chlamydia trachomatis infection, which can cause severe ocular disease or urogenital infections that compromise fertility. Wang et al. (p. 1670) profiled the humoral immune response to C. trachomatis infection to identify immunodominant Ags that could be used for vaccine development. The authors developed a proteome array consisting of 908 of the 918 possible open reading frames in the C. trachomatis genome and assessed the reactivity of Abs from 99 women with urogenital C. trachomatis infection to these potential Ags. A total of 719 Ags were recognized by at least one of the antisera tested; of these, 27 Ags were identified as immunodominant based on their specific recognition by Abs from >50% of the patients. Ab binding to 10 of these immunodominant Ags appeared to be conformation dependent. Comparison of the Ags recognized by human antisera with those recognized by Abs of mice and rabbits immunized with inactivated C. trachomatis bacteria allowed the identification of infection-dependent Ags. These Ags were only produced during live infection and were not necessarily incorporated into infectious particles. The use of these infection-dependent Ags may augment vaccine effectiveness, because inactivated whole organism-based vaccines have not been able to induce protection in humans.

The costimulatory molecule LIGHT is a member of the TNF superfamily of cytokines and acts through two receptors: the lymphotoxin-βR (LTβR) and the herpesvirus entry mediator. Polymorphisms in the gene encoding human LIGHT may modulate its activity and, thus, affect its potential as a therapeutic agent. Cheung et al. (p. 1949) assessed the activity of two variant forms of LIGHT that contained the amino acid substitutions E241K and S32L. E241K was found in LIGHT’s receptor-binding domain and altered its avidity for LTβR, whereas S32L was located in its cytosolic region and affected its stability. Heterotrimeric complexes of these LIGHT variants demonstrated increased avidity for LTβR and decreased avidity for the LIGHT competitive inhibitor decoy receptor 3 (DcR3) compared with wild-type trimers. Decreased LIGHT:DcR3 avidity reduced DcR3-mediated inhibition of LTβR signaling. Thus, these genetic variations in LIGHT can cause both a direct increase in LTβR signaling and a reduction in its inhibition via DcR3, which the authors propose could amplify inflammatory disease. In agreement with this idea, free DcR3 was overrepresented in the synovial tissues of patients with rheumatoid arthritis. Thus, these and other LIGHT polymorphic variants could augment antiviral defenses but could also enhance susceptibility to autoimmune diseases or cancer.

Effective protection against pneumococcal infection requires the prevention of nasal colonization. Although a successful vaccine against several strains of pneumococci is in wide use, infections with other strains of these bacteria are becoming prevalent. New protective strategies are necessary, and vaccines containing pneumococcal surface protein A (PspA) may be superior to current formulations in preventing nasal colonization. Fukuyama et al. (p. 1755) analyzed mice given a nasal vaccine consisting of PspA and an adjuvant to determine whether secretory IgA Abs (S-IgA) were involved in protection against colonization. Vaccinated wild-type mice produced high levels of PspA-specific IgG and IgA, and their CD4+ T cells produced high levels of IL-4 but little IFN-γ. Compared with wild-type mice, IgA/ mice generated higher levels of PspA-specific IgG following immunization, and their CD4+ T cells produced higher levels of IL-4 and IFN-γ. Although vaccination protected wild-type mice from nasal colonization with Streptococcuspneumoniae, IgA/ mice were colonized by large numbers of bacteria. Supporting this observation, PspA-specific S-IgA prevented S. pneumoniae colonization and neutralized pre-existing bacteria in the nasal passages. Integrating this identification of S-IgA’s vital role in vaccine-induced protection against pneumococcal colonization with knowledge of antibacterial cellular responses will be useful for the development of a broadly effective pneumococcal vaccine.

The role of the inflammasome in innate immunity has been studied in depth, but its involvement in adaptive immunity to infection is less clear. In this issue, Dunne et al. (p. 1711) examined the involvement of the inflammasome in protective adaptive immunity to Bordetella pertussis. Following B. pertussis infection, IL-1β, which is produced via inflammasome activation, was required for the Ag-specific production of IL-17 and for effective bacterial clearance. This IL-1β production was induced in dendritic cells by the B. pertussis virulence factor adenylate cyclase toxin (CyaA) through NALP3 and caspase-1 activation. The mechanism of inflammasome activation by CyaA was found to involve its pore-forming activity but not its adenylate cyclase activity. Completing the pathway, the authors determined that CyaA promoted B. pertussis-specific Th17 responses that were required for the clearance of infection. This study provides an important link between the inflammasome and pathogen-specific Th17 responses and demonstrates that bacterial virulence factors, such as CyaA, can augment host adaptive immune responses in addition to their known roles in subverting host immunity.

In experimental autoimmune encephalomyelitis, the related chemokines CXCL9 and CXCL10 are involved in positioning inflammatory cells in the CNS. IFN-γ induces the expression of both of these chemokines; however, in many inflammatory CNS diseases, CXCL9 expression is restricted to microglia, whereas CXCL10 is found in both microglia and astrocytes. Ellis et al. (p. 1864) sought to determine how IFN-γ differentially induces cell type-specific expression of CXCL9 and CXCL10 in these cells. Treatment of microglia with cycloheximide did not prevent chemokine expression, suggesting that the differential expression of CXCL9 and CXCL10 was regulated at the transcriptional level. In support of this hypothesis, the transcription factor PU.1 was constitutively expressed in the nuclei of microglia but not astrocytes in vitro and in vivo in brains of both healthy mice and those with experimental autoimmune encephalomyelitis. PU.1 and STAT1 were both found to be bound to the Cxcl9 promoter and were required for IFN-γ–induced expression of CXCL9 in microglia. However, STAT1 was also required for CXCL10 expression. Ectopic expression of PU.1 in an astrocyte-like cell line induced CD11b expression and caused these cells to respond to IFN-γ by upregulating Cxcl9. These data advance our understanding of cell positioning during CNS inflammation by demonstrating that PU.1 controls microglia-specific expression of CXCL9.

Summaries written by Jennifer Hartt Meyers, Ph.D.