Dendritic cells (DCs) are able to take up, process, and present exogenous Ags loaded onto MHC class I molecules to T cells through the process of cross-presentation. The aim of the study by Wagner and Cresswell (p. 686) was to examine how DC maturation prior to Ag encounter modulates the cross-presentation capacity of the cells. The authors used an in vitro system consisting of apoptotic herpes simplex virus-1–infected cells as the source of the Ag, stimulation with ligands for TLRs or nucleotide-binding oligomerization domain-like (Nod) receptors as the DC maturation signals, and IL-2 production by a T cell hybridoma as the readout. Pure LPS preparations enhanced cross-presentation while suppressing MHC class II presentation. This effect was dependent on signaling through MyD88 and TRIF. In contrast, less pure LPS preparations inhibited cross-presentation, suggesting that contaminants such as peptidoglycan were responsible for the strong inhibitory effect. Indeed, direct stimulation of DCs with peptidoglycan blocked cross-presentation through Nod signaling but did not affect MHC class II presentation. These results reconcile previously reported conflicting data on the cross-presentation ability of mature DCs and suggest that different microbial products might have opposite influences on DC function.

Recent research has indicated the existence of a B cell population that regulates immune responsiveness to infections via IL-10 production. Moreover, the cells had a protective effect in animal models of acute autoimmunity initiated by pathogen or Ag injection. In this issue, Teichmann et al. (p. 678) evaluated the relevance of IL-10–secreting B cells in the context of a spontaneous chronic autoimmune disease such as lupus. The authors deleted the Il10 gene in the B cells of the lupus-prone MRL.Faslpr mice to generate the B-IL10−/− strain, which was compared with the control IL10fl/fl strain in a series of studies. Lack of IL-10 secretion by B cells did not affect B cell homeostasis or function, nor did it alter T cell activation or differentiation. B-IL10−/− and control mice developed lupus spontaneously, and the disease manifestation and severity, as well as the survival of the mice, were comparable between the two groups. Accordingly, expression of the Il10 gene in the MRL.Faslpr mice was found predominantly in T cells and macrophages. The authors conclude that B cell-derived IL-10 does not regulate the establishment of lupus in the MRL.Faslpr model, which resembles the chronic nature of the human disease. This finding should be considered in the development of B cell-targeted therapies for autoimmune disorders.

Genetic variations in the TLR genes, including multiple single nucleotide polymorphisms, have been correlated with disease susceptibility. In TLR3, the Leu412Phe variant results in a sequence change affecting the receptor’s function upon binding of viral dsRNA. Sironi et al. (p. 818) examined the role of the Leu412Phe variant in protection against HIV-1 infection. By genotyping a cohort of 102 Spanish individuals, who were drug users and seronegative despite exposure to the virus, the authors found a significantly higher frequency of individuals carrying at least one 412Phe allele relative to matched healthy controls. Similar results were obtained by genotyping a cohort of individuals from a different geographic area who were exposed to HIV-1 through sexual activity. In vitro infection assays supported the genetic findings, as PBMCs from individuals heterozygous or homozygous for the variant supported lower levels of HIV-1 replication when compared with cells from Leu/Leu homozygotes. In addition, PBMCs carrying the 412Phe allele had enhanced responsiveness to TLR3 stimulation as shown by increased production of proinflammatory cytokines, although the levels of TLR3 expression in resting or activated cells were comparable among the groups examined. The genotype-phenotype association analysis indicates that this TLR3 polymorphism might contribute to individual resistance to HIV-1 infection.

Proteins and polysaccharides (PS) are classically considered T cell-dependent (TD) and T cell-independent (TI) Ags, respectively. However, this classification derives mostly from studies with purified Ags and does not take into consideration the fact that pathogens, including bacteria, are complex structures coexpressing multiple proteins and PS Ags. The report by Arjunaraja et al. (p. 569) examines the requirements for primary and secondary Ab responses to intact Neisseria meningitidis serogroup C (MenC), a Gram-negative bacterium, or to soluble PS isolated from the same bacterium (MCPS). Immunizations with the two Ags elicited anti-MCPS Ig responses characterized by different titers, Ab isotypes, and kinetics. In addition, the primary and secondary IgG responses to intact MenC were TI and TD, respectively, and the secondary response was dependent on CD28, CD40L, and ICOS costimulation. TLR4 signaling, but not TLR2 or MyD88 signaling, was required for the generation of high IgM and IgG titers. Interestingly, the results were markedly different from those previously obtained by the authors using intact Streptococcus pneumoniae, a Gram-positive bacterium. Taken together, these observations indicate that the structure and composition of an Ag dictate the profile of the elicited antibacterial humoral response, with a wide range of variation in immunity.

Complement activation through the alternative pathway is critical to the development of airway hyperresponsiveness (AHR). However, endogenous factor H (fH), a potent inhibitor of the alternative pathway, cannot completely prevent the establishment of asthma. To clarify this discrepancy, Takeda et al. (p. 661) examined the effects of agents that either enhanced or blocked the interaction of fH with tissues during allergic responses in the lung. Endogenous fH was found in the airways of mice that developed allergen-induced AHR, but not in control mice. Blocking the tissue-binding function of fH with an antagonist prior to the provocative secondary allergen challenge increased complement activation and tissue inflammation. Conversely, protection of mice in primary and secondary challenge models of AHR was achieved by administration of the fusion protein CR2-fH, which consisted of the inhibitory region of fH linked to the iC3b/C3d binding region of complement receptor 2 (CR2) and was thus able to target relevant pathological sites. These data demonstrated that the limited efficacy of endogenous fH was due to deficient delivery of the factor to the sites of complement activation and that targeted alternative complement inhibitors can prevent the development of AHR as well as ameliorate established disease. CR2-based therapeutics may represent a promising new approach for the treatment of asthma.

CD4+ T cells differentiate into various subsets, including Th1, Th2, Th17, and T regulatory (Treg) cells characterized by the expression of distinctive transcription factors and cytokines and well-defined functional profiles. In recent years, based on in vitro observations, it has become apparent that these subsets may not be terminally differentiated, but may acquire different phenotypes and functions depending on the cytokine milieu to which they are exposed. Panzer et al. (p. 615) conducted studies to demonstrate that functional conversion of the Th subsets can be achieved in vivo. The authors adoptively transferred in vitro polarized or ex vivo isolated Ag-specific Th1, Th17, or Treg cells into recipient mice that were subsequently infected with Nippostrongylus brasiliensis, a helminth known to induce a strongly polarized Th2 response. The experiments showed that a few days after infection, the majority of the Th1 cells lost the capacity to produce IFN-γ and instead expressed IL-4; similarly, Th17 cells became Th2 polarized. In contrast, Treg cells were less susceptible to conversion to a Th2 phenotype, as IL-4 expression could not be induced. This report highlights the functional plasticity of Th1 and Th17 cells, and suggests a mechanistic explanation for the beneficial effect of helminth infections in patients with autoimmune diseases, as the infections may decrease the number of pathological effector T cells by repolarizing them toward a Th2 phenotype.

Summaries written by Bernardetta Nardelli, Ph.D.