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Intestinal cryptopatch development
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2 heterotrimers on inducer cells and LTR on stromal cells. Similar interactions have not been demonstrated for cryptopatches (CP), a third type of lymphoid aggregate found in the small intestine. Taylor et al. (p. 7183
) found by immunostaining with anti-c-kit Abs that crypts of small intestine from LT–/– mice lacked CP and by histological staining that LTR–/– mice lacked lymphoid aggregates. However, mice deficient in NF-
B-inducing kinase had normal CP but no ILF. CD132 mice, which do not have peripheral lymph nodes or PP, rarely developed CP. Such mice also lacked splenic germinal centers after irradiation and reconstitution with T cell-depleted LT–/– bone marrow. In contrast, irradiated CD132 mice reconstituted with wild-type bone marrow developed CP and had normal-appearing spleens. LT–/– mice made chimeric with T cell-depleted wild-type bone marrow developed both CP and ILF. Irradiated CD132 mice that received a 1:1 mixture of T cell-depleted wild-type and LT–/– bone marrow developed CP and ILF consisting of cells from both donors. VCAM-1+ cells were detected by immunostaining in the periphery of wild-type CP and in the CP and the B cell area of ILF of bone marrow-reconstituted CD132 mice. The authors suggest that cell interactions dependent on LT and LTR initiate CP development independent of NF-B-inducing kinase and that novel VCAM-1+ stromal cells are involved in CP and ILF development. Inducing anergy
T lymphocytes that are stimulated through the TCR in the absence of CD28 costimulation become anergic and do not produce IL-2. However, the molecular factors that mediate anergy have not been identified. Harris et al. (p. 7331 ) used gene array screening to identify high level expression of early growth response gene-2 (Egr-2), a zinc-finger transcription factor, both in an Ag-challenged mouse CD4+ T cell line anergized with immobilized anti-CD3 mAb and in fully activated T cells, but not in mock-stimulated controls. Only the anergic cells maintained high level Egr-2 mRNA expression for 5 days and Egr-2 protein expression for 9 days. Exposure of anergic cells to exogenous IL-2 up to 5 days poststimulation resulted in loss of Egr-2 protein. T cells in which the Egr-2 gene had been silenced by small interfering RNA (siRNA) before anergy induction had significantly lower levels of Egr-2 protein and had greater proliferation, IL-2 production, and ERK phosphorylation than anergic T cells that had not received siRNA. Electroporation of siRNA into T cells 5 days after anergy induction reduced Egr-2 protein levels but did not restore Ag responsiveness. The data indicate that Egr-2 contributes to the induction and maintenance of the anergic state in T lymphocytes and that addition of IL-2 abolishes anergy.
Streptococcus pneumoniae virulence factor
Removal of Streptococcus pneumoniae occurs through phagocytosis of bacteria coated with C cleavage products or Ab. Pneumococci, in turn, use their surface protein A (PspA) to shield themselves from C deposition and to increase their virulence. Yet, the specific C receptors involved in host defense are not known. Ren et al. (p. 7506 ) found that mice deficient in factor D (lacking an alternative C pathway) infected with either PspA+ or PspA– S. pneumoniae had lower survival rates than wild-type controls. Clearance of PspA– pneumococci was delayed and survival was reduced in mice lacking complement receptors 1 and 2 (CR1/2–/–) compared with controls. In contrast, mice lacking CR3 or CR4 had higher death rates after infection with PspA+ pneumococci, yet had reduced clearance but complete survival after infection with PspA– bacteria. Mice deficient in LFA-1 or CD18 cleared both forms of pneumococci faster and had slightly longer or equal survival times, respectively, than wild-type animals. Infection-resistant CD18–/– mice had higher levels of naturally occurring anti-pneumococcal Abs than controls, whereas susceptible CD1/2–/– mice had lower levels of anti-phosphocholine Abs. More C3, in the form of iC3b, was deposited on PspA– bacteria than on PspA+ bacteria incubated with normal mouse or human serum. The authors conclude that PspA interferes with the alternative C pathway that uses CR1/2, CR3, and CR4 in host defense against S. pneumoniae infection.
Intestinal T cells in human infants
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transcript, TdT, and RAG were found by PCR in all cDNA samples prepared from intestines of infants 6 mo old or younger. TCR -chain junctional sequences showed that the small intestine TCRBV6 and TCRBV12 repertoire was polyclonal, whereas the TCRBV4 repertoire was monoclonal at all ages; in contrast, the TCRBV6 and TCRBV4 repertoire was polyclonal in the large intestine. The findings indicate that large numbers of immature epithelial and mucosal T cells are present in the intestine at birth and differentiate to a polyclonal population during the first 12–18 mo of human development. Neutrophil recruitment and transmigration
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-activated monolayer transmigrated within minutes in the absence of chemoattractants or shear stress. Neutrophil adhesion, arrest, and transendothelial migration (TEM) in the presence of continuous physiological shear stress increased on resting HUVEC overlaid with the lipid chemoattractant platelet-activating factor (PAF); TEM was prevented by pre-exposure of the HUVEC to a PAF-R antagonist. Pre-exposure of the neutrophils to PAF or the antagonist had no effect. Neutrophil TEM through PAF-presenting moderately activated HUVEC was more rapid under shear flow, was partially dependent on integrins expressed on HUVEC, and was prevented by addition of IL-8. Electron microscopic analyses demonstrated neutrophil invaginations into nonactivated and moderately activated HUVEC surfaces and junctions in response to shear flow; no invaginations were seen in the absence of shear stress. Approximately 5% of these invaginations resulted in TEM. The picture that emerges from the two laboratories is that neutrophil expression of PDE4B and PDE4D cooperate to control migration to the inflamed lung. Subsequent TEM is dependent on integrin interactions, state of endothelial cell activation, and shear stress signals. Peptidoglycan recognition
Organisms use host pattern recognition receptors to discriminate among, and defend against, invading microbes. However, the specific bacterial products recognized are not clearly defined. Stenbak et al. (p. 7339 ) used a combination of Drosophila cell culture and in vivo assays to analyze the specific structural components of peptidoglycans (PGs) recognized by a Toll-independent signaling cascade called the immune deficiency (Imd) pathway. Previously, the authors had shown that diaminopimelic acid (DAP)-containing PGs from Gram-negative and Gram-positive bacteria stimulated the Imd pathway via a specific PG recognition protein (PGRP). PGs from other Gram-positive bacteria in which lysine replaced DAP stimulated the Toll pathway but not the Imd pathway via a different PGRP. Reporter plasmids expressing pathway-specific antibacterial peptide genes confirmed those results in flies microinjected with purified PGs, and RT-PCR confirmed gene activation in a Drosophila cell line treated with PGs. By analyses of various digestion products and synthetic analogues, the authors determined that the minimal optimum motif for Imd pathway activation was a peptide containing N-acetylglucosamine plus N-acetylmuramic acid with a 1,6-anhydro bond that was connected to DAP by a 2-aa bridge. This PG motif is specific to Gram-negative bacteria. Modification of the sugar moieties, the anhydro bond, or the third amino acid (DAP) reduced Imd pathway induction.
HIV-induced DC maturation
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
and the Lymphotoxin Receptor
T Cells Differentiate and Rearrange Antigen Receptor Genes In Situ in the Human Infant
2 Integrin Occupancy at Apical Endothelial Contacts Combine with Shear Stress Signals to Promote Transendothelial Neutrophil Migration
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