MASP-1, the Lectin Leader
The complement system includes the classical, alternative, and lectin pathways, each of which is triggered by different molecular mechanisms. Mannan-binding lectins (MBLs) or ficolins form complexes with different MBL-associated serine proteases (MASPs) and bind to carbohydrate or glycoprotein ligands on microbes to activate the lectin pathway. Degn et al. (p. 3957) now better define roles for MASP-1 in the lectin pathway using both clinical samples and biochemical analysis. A patient identified with a nonsense mutation in MASP1 did not have detectable serum levels of any of the three MASP proteins (MASP-1, MASP-3, and MAp44) encoded by this gene. The alternative pathway functioned normally in the sera of this patient, despite previous data indicating a role for MASP-1 and MASP-3 in this pathway. In contrast, the lectin pathway was defective in this MASP1−/− patient. Further analysis using in vitro reconstitution assays demonstrated that MASP-1 was required for activation of the lectin pathway. At physiological levels, MASP-1 increased activation of the lectin pathway by activating MASP-2, and this transactivation was likely caused by complexes formed by MASP-1, MASP-2, and MBL. Together these results discern a role for MASP-1 in activation of the lectin pathway in humans.
Airway Adjuster
The molecular mechanisms that contribute to airway hyperresponsiveness (AHR) and asthma are not well understood, but recent studies have linked several members of the a disintegrin and metalloproteinase (ADAM) enzyme family to AHR. ADAM with thrombospondin motifs 12 (ADAMTS12) has been characterized recently as an asthma susceptibility gene in humans, and Paulissen et al. (p. 4135) developed Adamts12−/− mice to better understand its role in allergen-induced AHR. Exposure of wild-type mice to either OVA or house dust mite (HDM) allergens induced expression of Adamts-12 mRNA in the lungs. Adamts12−/− mice developed more severe AHR than wild-type mice following OVA or HDM challenge, which was associated with greater eosinophil infiltration in airway tissues and higher levels of allergen-specific IgG1 and IgE. In addition, mast cell recruitment and levels of ST2 and its ligand, IL-33, were higher in Adamts12−/− mice in response to challenge with these allergens. Overall, these observations indicate that Adamts12 may modulate inflammation that contributes to AHR and asthma and thus protect airways against excessive inflammation.
Half Life—The Peptide Predictor
CD4+ T cells are activated during viral infection in part through recognition of viral peptides presented by MHC class II (MHC II) molecules on APCs. Following proteolytic cleavage of viral proteins, peptides are loaded onto MHC II molecules through a peptide exchange process involving the nonclassical MHC II molecule HLA-DM (DM). Yin et al. (p. 3983) now assess the role of HLA-DM in peptide selection during vaccinia virus infection of human CD4+ T cells. They measured multiple binding properties, including the IC50, intrinsic disassociation half-life, DM-mediated disassociation half-life, and DM-susceptibility, of HLA-DR1–restricted epitopes derived from the A10L viral core protein relative to nonepitopes. All of these properties differed between epitopes and nonepitopes, although the DM-mediated half-life differed the most significantly. The DM-mediated half-life of HLA-DR1–A10L peptide complexes was the most robust predictor of CD4+ T cell epitopes, such that complexes with longer DM-mediated half-lives were associated with more immunodominant epitopes. This relationship was confirmed with peptides from other vaccinia virus proteins. Together, these results indicate that the DM-mediated dissociation half-life is an independent indicator that predicts peptide immunogenicity.
Autotaxin Aids Migration
The migration of naive T cells from the blood to secondary lymphoid organs (SLOs) can occur through high endothelial venules (HEVs) following a series of events that include rolling and arrest of T cells on the endothelial surface, intraluminal crawling, and transendothelial migration (TEM). Zhang et al. (p. 3914) now describe mechanisms by which the ectoenzyme autotaxin (ATX) contributes to these processes. Previous studies have shown that ATX is secreted by HEV endothelial cells (ECs) and can bind to T cells that have been activated by chemokines. In addition, ATX catalyzes a reaction that converts lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a bioactive lipid that has been observed to impact T cell migration. In this study, mice treated with the ATX inhibitor HA130 showed reduced T cell migration across HEVs in lymph nodes. Ex vivo studies showed that LPA alone or ATX combined with LPC could induce polarization and motility of naive T cells. LPA or ATX/LPC treatment could also promote TEM of T cells immobilized on ECs by integrin interactions under physiologic shear flow conditions. ATX binding was detected on the surface of T cells, particularly on the leading edge of polarized cells, and binding was enhanced by the presence of Mn2+, suggesting an interaction mediated by integrins. The authors propose a model in which localized ATX binding stimulates LPA production and thus promotes TEM. Thus, the ability of ATX to catalyze LPA formation plays a pivotal role in TEM of activated T cells.
Switch Sequence Preference
B cell activation includes the generation of Ab diversity via somatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes by activation-induced cytidine deaminase (AID). The Ig H chain locus undergoes CSR and SHM at switch (S) regions that are characterized by repetitive sequences, but the contribution of the sequences within S regions is not well understood. To assess the contribution of S region sequence to AID targeting independent of Igh cis regulatory elements, Chen et al. (p. 3970) used a knock-in mouse model in which a core Sγ1 region was inserted into the first intron of Bcl6. Bcl6 is involved in germinal center (GC) formation and is a non-Igh target of AID. The authors determined that the first intron of Bcl6 is an inefficient site of AID-mediated SHM. In GC B cells of Bcl6Sγ1/+ heterozygous mice, the Bcl6Sγ1 allele had a greater frequency of SHM than the wild-type Bcl6 allele. Relative to wild-type mice, the Sγ1 region in Bcl6Sγ1/ Sγ1 mice showed greater recruitment of AID and RNA polymerase II molecules. These results suggest that nucleotide sequences of S regions contribute to AID targeting, thus indicating another mechanism by which CSR and SHM are mediated.
Dicing in the Thymus
Immature thymocytes develop into mature TCR-expressing T cells in the thymus through a series of steps guided by cells that form the thymic stroma, including thymic epithelial cells (TECs). MicroRNAs (miRNAs) are small noncoding RNAs recognized for their ability to modulate mRNA stability and translation and influence manifold biological mechanisms. Zuklys et al. (p. 3894) have assessed the effect miRNAs have on TEC function and T cell differentiation using a mouse strain with a TEC-targeted deficiency in Dicer (Foxn1-Cre::Dicerfl/fl), an enzyme required for miRNA generation. Thymic cellularity, as well as development of double positive (DP) thymocytes and single positive mature T cells, was significantly reduced in Foxn1-Cre::Dicerfl/fl mice relative to controls. In particular, Dicer deficiency in cortical TECs dramatically compromised T cell lineage commitment of early thymic progenitors, and was also associated with less effective maturation and positive selection of DP thymocytes. Gene expression profiling suggested that multiple processes were affected by Dicer deficiency in TECs, including the expression of genes involved in transcription, differentiation, and cell signaling. These findings suggest that T cell differentiation and selection, as well as development of central tolerance, are dependent on miRNA-mediated regulation of gene expression in TECs.
- Copyright © 2012 by The American Association of Immunologists, Inc.
