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J Immunol 2012; 189:3785-3786; ; doi: 10.4049/jimmunol.1290061 This information is current as http://www.jimmunol.org/content/189/8/3785 of October 1, 2021.

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. MASP-1, the Lectin Leader AHR and asthma and thus protect airways against excessive inflammation. he complement system T includes the classical, al- Half Life—The Peptide Predictor ternative, and lectin path- 1 ways, each of which is triggered by D4 T cells are activated during viral infection in different molecular mechanisms. C part through recognition of viral peptides presented Mannan-binding lectins (MBLs) or by MHC class II (MHC II) molecules on APCs. ficolins form complexes with differ- Following proteolytic cleavage of viral proteins, peptides are ent MBL-associated serine proteases loaded onto MHC II molecules through a peptide exchange (MASPs) and bind to carbohydrate process involving the nonclassical MHC II molecule HLA- or glycoprotein ligands on microbes to activate the lectin DM (DM). Yin et al. (p. 3983) now assess the role of pathway. Degn et al. (p. 3957) now better define roles for HLA-DM in peptide selection during vaccinia virus infection 1 MASP-1 in the lectin pathway using both clinical samples and of human CD4 T cells. They measured multiple binding Downloaded from biochemical analysis. A patient identified with a nonsense properties, including the IC50, intrinsic disassociation half- mutation in MASP1 did not have detectable serum levels of life, DM-mediated disassociation half-life, and DM-suscept- any of the three MASP proteins (MASP-1, MASP-3, and ibility, of HLA-DR1–restricted epitopes derived from the MAp44) encoded by this gene. The alternative pathway func- A10L viral core protein relative to nonepitopes. All of these tioned normally in the sera of this patient, despite previous properties differed between epitopes and nonepitopes, al- data indicating a role for MASP-1 and MASP-3 in this though the DM-mediated half-life differed the most signifi- http://www.jimmunol.org/ pathway. In contrast, the lectin pathway was defective in this cantly. The DM-mediated half-life of HLA-DR1–A10L 2 2 1 MASP1 / patient. Further analysis using in vitro reconsti- peptide complexes was the most robust predictor of CD4 tution assays demonstrated that MASP-1 was required for T cell epitopes, such that complexes with longer DM-me- activation of the lectin pathway. At physiological levels, diated half-lives were associated with more immunodominant MASP-1 increased activation of the lectin pathway by acti- epitopes. This relationship was confirmed with peptides from vating MASP-2, and this transactivation was likely caused by other vaccinia virus proteins. Together, these results indicate complexes formed by MASP-1, MASP-2, and MBL. To- that the DM-mediated dissociation half-life is an independent gether these results discern a role for MASP-1 in activation of indicator that predicts peptide immunogenicity. the lectin pathway in humans. by guest on October 1, 2021 Autotaxin Aids Migration Airway Adjuster he migration of he molecular mechanisms that contribute to airway T naive T cells hyperresponsiveness (AHR) and asthma are not well from the blood T to secondary lymphoid understood, but recent studies have linked several members of the a disintegrin and metalloproteinase (ADAM) organs (SLOs) can occur enzyme family to AHR. ADAM with thrombospondin motifs through high endothelial 12 (ADAMTS12) has been characterized recently as an venules (HEVs) follow- asthma susceptibility gene in humans, and Paulissen et al. ing a series of events that 2 2 (p. 4135) developed Adamts12 / mice to better understand include rolling and arrest its role in allergen-induced AHR. Exposure of wild-type mice of T cells on the endothelial surface, intraluminal crawling, to either OVA or house dust mite (HDM) allergens induced and transendothelial migration (TEM). Zhang et al. (p. 3914) 2 2 expression of Adamts-12 mRNA in the lungs. Adamts12 / now describe mechanisms by which the ectoenzyme autotaxin mice developed more severe AHR than wild-type mice fol- (ATX) contributes to these processes. Previous studies have lowing OVA or HDM challenge, which was associated with shown that ATX is secreted by HEV endothelial cells (ECs) greater eosinophil infiltration in airway tissues and higher and can bind to T cells that have been activated by chemokines. levels of allergen-specific IgG1 and IgE. In addition, mast cell In addition, ATX catalyzes a reaction that converts lyso- recruitment and levels of ST2 and its ligand, IL-33, were phosphatidyl choline (LPC) to lysophosphatidic acid (LPA), 2 2 higher in Adamts12 / mice in response to challenge with a bioactive lipid that has been observed to impact T cell these allergens. Overall, these observations indicate that migration. In this study, mice treated with the ATX inhibitor Adamts12 may modulate inflammation that contributes to 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 Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 TEM of T cells immobilized on ECs by integrin interactions www.jimmunol.org/cgi/doi/10.4049/jimmunol.1290061 3786 IN THIS ISSUE under physiologic shear flow conditions. ATX binding was Sg1 region in Bcl6Sg1/ Sg1 mice showed greater recruitment of detected on the surface of T cells, particularly on the leading AID and RNA polymerase II molecules. These results suggest edge of polarized cells, and binding was enhanced by the that nucleotide sequences of S regions contribute to AID 1 presence of Mn2 , suggesting an interaction mediated by targeting, thus indicating another mechanism by which CSR integrins. The authors propose a model in which localized and SHM are mediated. ATX binding stimulates LPA production and thus promotes TEM. Thus, the ability of ATX to catalyze LPA formation Dicing in the Thymus plays a pivotal role in TEM of activated T cells. mmature thymocytes develop into mature TCR-ex- Switch Sequence Preference I pressing T cells in the thymus through a series of steps guided by cells that form the thymic stroma, cell activation including thymic epithelial cells (TECs). MicroRNAs B includes the (miRNAs) are small noncoding RNAs recognized for their generation of ability to modulate mRNA stability and translation and Ab diversity via somatic influence manifold biological mechanisms. Zuklys et al. hypermutation (SHM) (p. 3894) have assessed the effect miRNAs have on TEC and class switch re- function and T cell differentiation using a mouse strain with combination (CSR) of a TEC-targeted deficiency in Dicer (Foxn1-Cre::Dicerfl/fl), an Ig genes by activation- enzyme required for miRNA generation. Thymic cellularity, Downloaded from induced cytidine de- as well as development of double positive (DP) thymocytes aminase (AID). The Ig H chain locus undergoes CSR and and single positive mature T cells, was significantly reduced in SHM at switch (S) regions that are characterized by repetitive Foxn1-Cre::Dicerfl/fl mice relative to controls. In particular, sequences, but the contribution of the sequences within S Dicer deficiency in cortical TECs dramatically compromised regions is not well understood. To assess the contribution of T cell lineage commitment of early thymic progenitors, and S region sequence to AID targeting independent of Igh cis was also associated with less effective maturation and positive http://www.jimmunol.org/ regulatory elements, Chen et al. (p. 3970) used a knock-in selection of DP thymocytes. Gene expression profiling mouse model in which a core Sg1 region was inserted into the suggested that multiple processes were affected by Dicer first intron of Bcl6. Bcl6 is involved in germinal center (GC) deficiency in TECs, including the expression of genes in- formation and is a non-Igh target of AID. The authors de- volved in transcription, differentiation, and cell signaling. termined that the first intron of Bcl6 is an inefficient site of These findings suggest that T cell differentiation and selec- 1 AID-mediated SHM. In GC B cells of Bcl6Sg1/ heterozy- tion, as well as development of central tolerance, are de- gous mice, the Bcl6Sg1 allele had a greater frequency of SHM pendent on miRNA-mediated regulation of gene expression than the wild-type Bcl6 allele. Relative to wild-type mice, the in TECs. by guest on October 1, 2021