Helicobacter pylori chronically infects the stomachs of about half of the world’s population and is a major cause of peptic ulcers and gastric cancer. Infection is maintained despite the generation of both innate and adaptive immune responses, suggesting the existence of multiple immune evasion mechanisms. Recently, arginase II (Arg2), which antagonizes macrophage production of NO, has been found to be upregulated by H. pylori and to impair bacterial killing by macrophages in vitro. To determine the applicability of this mechanism to immune evasion during chronic infection, Lewis et al. (p. 3632) examined H. pylori infection in Arg2−/− mice. Induction of macrophage Arg2 expression was observed in the stomachs of wild-type (WT) mice following H. pylori infection. Compared with these WT mice, Arg2−/− mice had significantly decreased levels of H. pylori colonization that correlated with increased gastritis. H. pylori-infected Arg2−/− mice, compared with infected WT mice, also demonstrated augmented production of the proinflammatory cytokines IFN-γ, IL-12, and IL-17a, decreased production of IL-10, and decreased macrophage apoptosis. During chronic infection, Arg2−/− mice had more inducible NO synthase-expressing macrophages, corresponding to increased NO synthesis, versus WT mice, suggesting a mechanism for the reduced levels of H. pylori colonization in these mice. These data may aid the development of strategies to prevent adverse outcomes of long-term H. pylori infection.

Control of lymphocyte entry into the lymph nodes (LNs) by the chemokine receptor CCR7 is important for the proper development of an adaptive immune response. Plasmacytoid dendritic cells (pDCs) are a subset of DCs that, like T cells, enter the LNs via high endothelial venules. Although CCR7 is known to be upregulated on pDCs following activation, it has been reported that resting pDCs do not express this receptor. Seth et al. (p. 3364) have found that resting pDCs not only express CCR7 but that it is important for their entry into the LN. CCR7-deficient mice demonstrated reduced pDC frequencies in the LNs and peripheral blood, but not the spleen or bone marrow. This observation led the authors to determine that resting pDCs expressed low levels of CCR7 capable of inducing migration in vitro. Adoptive transfer experiments comparing the migration of wild-type and CCR7−/− pDCs revealed a defect in the LN homing ability of CCR7−/− cells in both steady state and inflammatory conditions. Thus, by mediating pDC entry into the LNs, CCR7 may be involved in the major roles that these cells play in antiviral immunity and tolerance induction.

Chlamydia trachomatis is a common sexually transmitted pathogen for which a successful vaccine has not been developed. Vaccinations with dead elementary bodies (EBs) from C. trachomatis (in humans) or C. muridarum (in mice) have not been effective, whereas use of live C. muridarum EBs can elicit protective immunity. To address the mechanism mediating this protection, Yu et al. (p. 3615) compared the immune response to intranasal vaccination with live versus dead C. muridarum EBs. Both before and after C. muridarum challenge, mice vaccinated with live EBs demonstrated significantly more multifunctional IFN-γ+TNF-α+CD4+ T cells than did mice vaccinated with dead EBs, whereas animals immunized with dead EBs produced single-positive IFN-γ+CD4+ T cells. These data suggested that T cells coexpressing IFN-γ and high levels of TNF-α could be the effector cells responsible for protection. Further evidence of the efficacy of live EB vaccination was provided by immunoproteomic analysis of the C. muridarum-derived MHC class II peptides presented by dendritic cells (DCs) treated with live versus dead EBs. Live EB-pulsed DCs presented 45 peptides from 13 proteins, whereas dead EB-pulsed DCs presented only 6 peptides from 3 proteins, suggesting more efficient Ag presentation in response to live EB treatment. Knowledge of these factors contributing to protective antichlamydial immunity should provide a boost to vaccine development efforts.

Although DNA alkylating agents are commonly used in chemotherapy, their molecular mechanisms of antitumor activity have not been fully elucidated. Necrosis induced by chemotherapy causes the release of cellular contents, including high mobility group box 1 (HMGB1), which can trigger innate immunity. Because DNA alkylating therapy can induce tumor regression in the absence of adaptive immunity, Guerriero et al. (p. 3517) assessed the role of HMGB1 in this therapy-induced antitumor innate immune response. In athymic mice, treatment with the DNA alkylating agent cyclophosphamide (CP) induced regression of tumors expressing HMGB1, but not HMGB1−/− tumors or tumors treated with an HMGB1 neutralizing Ab. CP treatment of HMGB1-expressing, but not HMGB1−/−, tumors also resulted in the infiltration of large numbers of macrophages, neutrophils, and NK cells and the induction of granzyme activity, suggesting that HMGB1 stimulated innate immunity and served as a chemoattractant for these innate cells. HMGB1 could also promote the antitumor activity of M1 macrophages while suppressing the protumor responses of alternatively activated M2 macrophages. HMGB1 thus plays an essential role in the innate immune response to CP chemotherapy and consequent tumor clearance.

Coinfection with Mycobacterium tuberculosis and HIV can have deadly consequences. Development of effective treatment for coinfected individuals requires a more thorough understanding of how these pathogens interact with one another and with the host immune system. Mattila et al. (p. 3527) therefore analyzed the T cell cytokine responses of cynomolgus macaques coinfected with M. tuberculosis and SIV. The M. tuberculosis-specific T cell responses varied remarkably between animals and even within the same animal, similar to what would be expected in human populations; however, similar patterns in the responses were observed. Following SIV infection of latently M. tuberculosis-infected macaques, the frequency of T cells expressing IFN-γ and IL-2 transiently increased. Interestingly, there was also a spike in the frequency of IL-4–producing T cells, reported to be indicative of a poor prognosis in M. tuberculosis infection, that correlated with a decrease in the production of Th1 cytokines. The presence of multifunctional T cells has been connected to protection against HIV and SIV. However, in coinfected macaques, multifunctional Th1 cells were more plentiful in “early reactivators,” suggesting that these cells were associated with increased bacterial load rather than protection. Early reactivation of M. tuberculosis also correlated with an increased frequency of CD8+ T cells producing Th2 cytokines, compared with cells in late reactivating animals. Finally, granuloma T cell responses were found to differ significantly from those in the peripheral blood. This study is an important contribution toward the understanding of M. tuberculosis reactivation during HIV/SIV infection.

An important signaling cascade induced by T cell costimulation involves activation of PI3K and protein kinase B (PKB, also known as Akt) and mediates T cell expansion, differentiation, and survival. OX40, a TNFR superfamily member whose expression on T cells is induced after Ag recognition, has been shown to mediate sustained PI3K and PKB signaling. However, OX40 lacks the consensus motif by which other costimulatory molecules recruit PI3K. So et al. (p. 3547) therefore developed an in vitro system to elucidate the mechanism by which OX40 stimulation leads to PI3K/PKB activation. Stimulation of OX40 with OX40L induced the formation of a signaling complex that contained OX40, PI3K, PKB, and the adaptor molecule TRAF2 but did not include TCR or CD28 and formed independently of TCR engagement. Most PI3K and PKB activation, however, did require Ag recognition. TRAF2 was required for recruitment of these kinases to the OX40-containing complexes, and recruitment occurred within detergent-insoluble membrane lipid microdomains. These data identify a mechanism by which OX40 gathers signaling molecules to quantitatively enhance T cell activation.

The anti-inflammatory cytokine IL-10 can prolong chronic viral infections and can be produced by CD8+ T cells during acute respiratory infections. Very little is known about the production of this cytokine by CD8+ T cells, leading Trandem et al. (p. 3642) to assess whether IL-10 was produced by CD8+ T cells in acute viral encephalitis. In the course of infection with the J2.2-V-1 strain of mouse hepatitis virus, transient IL-10 production by both CD8+ and CD4+ T cells was observed in the brain during peak inflammation. The IL-10+ CD8+ T cells were virus specific and demonstrated increased cytolytic activity and pro-inflammatory cytokine production compared with IL-10 CD8+ T cells. Production of IL-10 required stimulation of CD8+ T cells with high doses of Ag and downstream signaling via the MAPK pathway. Consistent with these data, IL-10+ CD8+ T cells were found to be more highly activated than IL-10 CD8+ T cells. However, despite the hyperactivated, proinflammatory nature of these cells, the IL-10 they produced demonstrated suppressive activity in vitro and protected against virus-induced demyelination in vivo. Immunity to infections of the CNS must strike a balance between rapid pathogen clearance and prevention of tissue damage. This study suggests that IL-10 production by virus-specific CD8+ T cells in the brain may play a major role in maintaining this balance.

IgE, which is found in mucosal secretions, is involved in the development of allergic airway inflammation, but it is not known how allergen–IgE complexes might cross the respiratory epithelial layer to access effector cells such as mast cells. Palaniyandi et al. (p. 3484) have identified the low-affinity IgE receptor FcεRII (CD23) as the party responsible for IgE transcytosis in the airways. Respiratory epithelial cells were found to express the CD23b, but not the CD23a, isoform of this FcR, and IL-4 upregulated their CD23b expression. CD23 was found to specifically transport IgE and IgE-containing immune complexes (ICs) across polarized human airway epithelial monolayers, and this transcytosis was augmented by IL-4 stimulation. Transcytosis of IgE and IgE-containing ICs was also observed in primary human airway epithelial cells, supporting the in vivo relevance of these data. Following CD23-mediated transcytosis, the IgE-containing ICs were able to induce mast cell degranulation. CD23 may therefore act as an important player in the initiation of allergic responses by mediating the transport of allergen–IgE ICs across the airway epithelium.

Summaries written by Jennifer Hartt Meyers, Ph.D.