The mechanisms behind the detrimental effects of maternal infection during late gestation on fetal health and neurological development are poorly understood. Girard et al. (p. 3997) have observed that LPS-induced inflammation during late gestation in rats causes placental damage, fetal death, and neurological impairment in surviving offspring. Placental health was assessed by magnetic resonance imaging that quantified placental perfusion. Systemic LPS exposure caused a significant decrease in placental perfusion compared with placentas from untreated pregnant rats, and this imaging assessment was confirmed by histological findings. LPS treatment induced a significant increase in placental proinflammatory cytokines, especially IL-1β. Furthermore, maternal LPS exposure correlated with decreased fetal survival and birth weight, as well as abnormal forebrain white matter accumulation and altered motor control. Strikingly, IL-1β blockade achieved by coadministration of LPS and IL-1R antagonist curbed placental perfusion impairment and reduced the levels of fetal death and neurological damage. These results shed light on a link among excessive IL-1β production, placental destruction, and fetal brain damage, thereby suggesting that IL-1β blockade may be a potential therapeutic intervention for protecting fetuses from maternal inflammation.

Melatonin has been shown to have multiple effects on the immune system while also serving as a key regulator of circadian rhythms. Pedrosa et al. (p. 3487) now report that melatonin can protect activated CD4+ T cells from activation-induced cell death (AICD). Melatonin treatment of anti-CD3–stimulated T cell hybridoma cells or primary murine CD4+ T cells protected against AICD in a dose-dependent manner. AICD-sensitized human CD4+ T cells were also protected from apoptosis by melatonin. Melatonin inhibited apoptosis caused specifically by TCR/CD3 engagement and hindered anti-CD3–mediated expression of the apoptotic ligand CD95L. The mechanism of melatonin inhibition of CD95L expression involved the prevention of NFAT dephosphorylation by Ca2+/calmodulin-dependent calcineurin, thus preventing NFAT nuclear translocation and its activation of CD95L transcription. Conversely, melatonin did not impede a calcineurin-independent, constitutively active form of NFAT, thus confirming that melatonin blocks calcineurin-driven NFAT activation. Thus, melatonin appears to be able to protect CD4+ T cells from AICD and promote sustained T cell responses. Further investigation is needed to determine if chronic use of melatonin, especially in travelers or those with sleep disorders, may affect T cell responses adversely and cause autoimmunity.

Previous studies revealed a significant expansion of splenic regulatory T cells (Tregs) in NOD mice that were protected from diabetes by treatment with a chimeric Ig molecule carrying a diabetogenic amino acid sequence from glutamic acid decarboxylase (Ig-GAD1). Tartar et al. (p. 3377) have characterized a unique FoxP3+ RORγt+ T cell subset in NOD mice that can suppress diabetes. Two FoxP3+ populations were identified in the spleen following Ig-GAD1 treatment, one with intermediate FoxP3 expression (FoxP3int) and one with high FoxP3 expression. FoxP3int T cells were also detected in the pancreas. FoxP3intRORγt+ T cells expressed both CD62L, which was required for trafficking to the pancreas, and membrane-bound TGFβ (mTGFβ), a suppression mediator, which was essential to diabetes prevention in Ig-GAD1-treated NOD mice. Surprisingly, FoxP3intRORγt+ T cells were able to terminally differentiate in vitro into FoxP3+RORγt Tregs or FoxP3RORγt+ IL-17–expressing T cells. These observations highlight the functional contribution of a unique intermediate Treg population, which may be critical to containing autoimmune responses.

Phagocytosis of certain bacteria, including Bacterioides fragilis, initiates immune responses through oxidation of capsular polysaccharides that coat the bacterial surface. In particular, cleavage of a B. fragilis glycoantigen (GlyAg) via TLR2-dependent NO-mediated oxidiation activates T cells that recognize GlyAg fragments presented by MHC class II molecules. Lewis and Cobb (p. 3789) have found that GlyAg induced endosomal acidification, which facilitated protein Ag processing and TLR9 signaling. Endosomal acidification within murine macrophages or dendritic cells required NO-mediated oxidation of GlyAg, but was not dependent upon proton pump-driven acidification. Moreover, the endosomes acidified through NO-dependent GlyAg oxidation took up and processed protein Ag and were capable of CpG oligonucleotide recognition and signaling via TLR9. A negative feedback mechanism controlled the reaction rate of GlyAg oxidation, which slowed in the presence of high proton concentrations that are present following oxidation. This mechanism limited cleavage of GlyAg fragments to sizes appropriate for MHC class II presentation. This study provides a better understanding of the mechanisms by which GlyAg influences protein Ag processing and innate immunity, which may lead to improved antibacterial therapies.

Ag recognition by the BCR is essential for initiating T-dependent B cell responses. One lingering issue is the mechanism by which large particulate Ags, like bacteria and parasites, can be recognized by follicular B cells. Catron et al. (p. 3609) addressed this matter by following Ag-specific B cell responses in mice injected with 1 μM microspheres that were covalently linked to a model Ag, which was composed of a fusion protein of GFP with the Eα peptide covalently linked to hen egg lysozyme (EαGFP-HEL). C57BL/6 mice were adoptively transferred with anti-HEL transgenic B cells and immunized with EαGFP-HEL with LPS as an adjuvant. Anti-HEL–expressing B cells took up Ag without acquiring microspheres and subsequently formed peptide-MHC class II complexes and developed T-dependent B cell responses. Neither dendritic cells nor macrophages were required for Ag uptake by B cells. EαGFP-HEL–linked microspheres were restricted to the subcapsular sinus, and Ag-specific responses were not affected by preventing B cell migration to this site. Furthermore, Ag could be separated from microspheres in a protease-dependent manner. Taken together, B cell responses to large Ags may be dependent on proteolytic cleavage of Ags from the surface of particles, thus lending insight into how B cells initiate responses against large microbes.

Inhibitory receptors expressed by NK cells, including murine Ly49A, engage MHC class I (MHC I) molecules, which licenses NK cells to recognize and attack “missing self” cells that express little or no MHC I. Jonsson et al. (p. 3424) have examined the binding interactions required for licensing of Ly49A+ NK cells using a unique set of MHC-congenic hosts each expressing a different MHC I haplotype. IFN-γ production by activated Ly49A+ NK cells served as a functional readout of licensing. The authors confirmed that MHC haplotype H-2b weakly licensed NK cells, and H-2d induced strong licensing. Novel findings included observations that H-2q and H-2s caused weak licensing, but NK cells were strongly licensed through H-2r. The different levels of licensing by various MHC haplotypes correlated directly with the level of Ly49A tetramer binding to NK cells expressing these haplotypes. An inverse correlation was observed between licensing strength and the level of cis engagement of Ly49A by different MHC haplotypes. Intriguingly, a lower threshold of Ly49A-MHC I engagement was needed to inhibit effector functions of NK cells compared with licensing. Taken together, the strong binding interactions needed for Ly49A+ NK cell licensing suggests a mechanism that protects against NK cell autoreactivity.

Helios transcription factor mRNA has been shown previously to be restricted to FoxP3+ regulatory T cells (Treg cells). Thornton et al. (p. 3433) have characterized a unique Treg cell subpopulation expressing Helios with a novel anti-Helios mAb. Study of Helios protein expression during thymic development confirmed mRNA expression analysis in that nearly all CD4+CD8FoxP3+ thymocytes were Helios+. Surprisingly, in both humans and mice, only 70% of CD4+FoxP3+ Treg cells isolated from peripheral tissues expressed Helios. Induction of the differentiation of naive human or murine T cells into Treg cells by culture in the presence of TGF-β did not induce Helios expression. In vivo induction of OVA-specific Treg cells by Ag feeding also did not induce Helios. Furthermore, Helios did not appear to affect FoxP3 expression, nor did FoxP3 regulate Helios expression. Finally, Treg cells from Helios−/− mice showed suppressive activity similar to wild-type Treg cells. Thus, Helios may be a specific marker for natural Treg cells of thymic origin but is not directly required for their regulatory function. The abundance of Helios-negative peripheral Treg cells suggests that these cells develop outside of the thymus.

An abundance of IgA Abs against T cell-independent Ags inhabits the mucosa, but the mechanism and site of IgA class switch recombination (CSR) is not clear. Previous studies showed that CD40−/− mice had an almost normal number of IgA plasma cells in the lamina propria in spite of no detectable germinal centers (GCs) in the Peyer’s patches (PPs). In this issue, Bergqvist et al. (p. 3545) seek to define the site and mechanisms essential to T cell-independent IgA CSR. IgA CSR was measured by semiquantitative PCR of molecular markers of CSR and flow cytometric analysis. IgA CSR was confirmed in the PPs of both wild-type (WT) and CD40−/− mice, albeit at lower levels in CD40−/− mice. mRNA levels of the purported IgA switch factors BAFF, APRIL, and iNOS were similar in the PPs of CD40−/− and WT mice, despite the lack of GC formation in CD40−/− mice. Further analysis revealed that a large proportion of B cells in the PPs of WT and CD40−/− mice expressed intermediate levels of the GC marker GL7 (GL7int), and these B cells did not undergo somatic hypermutation (SHM). In contrast, PPs of WT mice were also enriched for B cells expressing high levels of GL7, and these cells had undergone extensive SHM and had entered GCs. These observations support a mechanism in which IgA CSR in the PPs precedes GC formation, but subsequent SHM is GC dependent, thus clarifying how IgA CSR can proceed in mice devoid of GCs.

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