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Uptake of gut luminal Ags
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MyD88 and liver regeneration
Liver regeneration following partial hepatectomy relies on induction of TNF-
and IL-6 signaling pathways. Although LPS activation of TLR4 is thought to trigger regeneration, it is not known if TLR4 is involved in gene induction and transcription factor activation. Campbell et al. (p. 2522
) found decreased serum levels of IL-6 in MyD88–/– mice 4 h after partial hepatectomy compared with wild-type, Tlr2–/–, Tlr4–/–, or Cd14–/– mice or mice heterozygous for any of the four genes. Only MyD88 –/– mice had decreased STAT-3 activation detected by phosphoimmunoblotting and EMSA analysis and decreased expression of IL-6/STAT-3 target genes and two acute phase response genes determined by RT-PCR. TNF- mRNA levels increased by 30 min in livers of wild-type, heterozygous, and homozygous animals following partial hepatectomy but not in livers of MyD88–/– mice. NF-
B activation occurred at 1 h after surgery in MyD88–/– mice compared with 30 min in controls. Measurements of hepatocyte DNA replication by BrdU incorporation did not differ among MyD88–/– mice and controls or among Helicobacter-free mice infected with either of two strains of Helicobacter. The authors conclude that LPS activation of MyD88, and not TLR4, is responsible for activation of TNF- and IL-6 pathways during liver regeneration.
IgA and Smad2
Activation of Smad2 and Smad3 proteins follows binding of TGF-
with its receptor and is critical for signal transduction. Investigation into any role of Smad proteins in B cell signaling has been hampered by the lethal phenotype of Smad–/– mice. Klein et al. (p. 2389
) developed mice with B cell-specific Smad2 inactivation (bSmad2–/–). No difference in total number of bone marrow cells or frequency of cells at most maturation stages in the spleen was seen between bSmad2–/– mice and bSmad2+/+ controls. However, bSmad2–/– mice had a 3-fold increase in IgM–IgD– B cell numbers in Peyer’s patches (PP), a 50% reduction in splenic transitional T2 and marginal zone B cells, and a 2-fold increase in B1a cells plus a 50% decrease in CD5high IgM– T cells in the peritoneal cavity. IgA serum levels were reduced 2-fold in naive bSmad2–/– mice; an Ag-specific IgA response was reduced up to 10-fold in TNP-immunized bSmad2–/– mice, and IgA Ab-secreting PP cells were reduced 5-fold. Excised circular DNA specific for IgA class switching were detected by RT-PCR in splenic B cells from bSmad2+/+ mice, but not from bSmad2–/– mice, after stimulation with LPS plus TGF- in vitro. LPS stimulated greater in vitro proliferation of bSmad2–/– vs bSmad2+/+ PP cells but not spleen cells, and TGF- inhibited proliferation of cells from the two organs of both strains of mice equally. By functional inactivation of Smad2 in B cells, the authors demonstrate a role for Smad2 in induction of an IgA response to TGF- signaling and in regulation of maturation or maintenance of peripheral B cells.
NK cells and tuberculosis
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T cells to control pulmonary tuberculosis. Although decreases in NK cell activity and T cell numbers occur in patients with active pulmonary tuberculosis, a relationship between NK and T cells has not been established. Zhang et al. (p. 2610
) found that T cells in PBMC samples with >15% CD56+ cells from human blood donors had greater proliferation in response to Ags of heat-treated M. tuberculosis plus IL-2 than T cells in PBMC samples with <5% CD56+ cells. Proliferation and T cell numbers decreased significantly in PBMC samples depleted of NK cells. Increased CD69 expression, cytotoxicity, and intracellular IFN- levels were measured for NK cells cultured with Ags plus IL-2 but not with Ags or IL-2 alone. Addition of anti-IFN- Ab did not alter the proliferative response, and exogenous IFN- did not increase T cell numbers in PBMCs depleted of NK cells. Transwell separation of NK cells from NK cell-depleted PBMCs resulted in reduced proliferation of T cells; addition of TNF-, GM-CSF, or IL-12 separately or in combination enhanced T cell proliferation. Confocal microscopy demonstrated that NK cell CD54, which was expressed more on cells treated with heat-treated Ags, polarized at the synapse with the T cell. Treatment of activated NK cells with anti-CD54 Ab decreased the number of T cells in NK-depleted PBMCs incubated with heat-treated Ags plus IL-2. The data demonstrate that T cells proliferate in response to NK cells activated by heat-treated Ags from M. tuberculosis by both cell contact-dependent and -independent mechanisms. A new lung DC population
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E+ DCs (E-DCs), and myeloid CD11bhigh-DCs, by anti-CD11c-magnetic bead enrichment of mouse lung digests. These and plasmacytoid DCs (pDCs) were the only I-A+ DCs found in lung. The profile of surface markers was different between E-DCs and pDCs. E-DCs expressed two adhesion molecules at high levels, several B7 molecules at moderate levels along with TLR2, and accessory molecules CD40 and Ox40L, whereas pDCs expressed low levels of costimulation molecules. An initial rapid burst of pinocytosis of FITC-dextran was seen with E-DCs compared with CD11bhigh-DCs. Both DC types stimulated OVA-specific T cell proliferation with soluble anti-CD3 mAb or OVA peptide, and both produced IL-12 when stimulated with TLR ligands, although with different responses to the same ligand. E-DCs were localized in airway mucosa at the parenchymal side of arteriole walls by mAb staining and confocal microscopy. Higher expression of Langerin and tight junction proteins in E-DCs than in CD11bhigh-DCs was detected by microarray and real-time PCR analyses and confirmed by immunostaining. Lungs of mice with OVA-induced asthma had higher numbers of E-DCs, with increased expression of costimulation molecules, and of CD11bhigh DCs than lungs of control mice. E-DCs within immunized lungs were adjacent to the basal lamina of the bronchial epithelium and arterioles, whereas CD11bhigh-DCs were found in proximal subepithelia and vascular wall in the immunized animals. The authors identify and characterize mucosal E-DCs as a DC population distinct from CD11bhigh-DCs within the mouse lung. Re-evaluating proteasome function
Eisenlohr and collaborators demonstrated that proteasome inhibitors enhance presentation of NP147–155, an influenza virus nucleoprotein (NP) epitope, and are required for processing a mutated NP147–155. In a follow-up to their work, Wherry et al. (p. 2249 ) looked at proteasome-independent and -dependent generation of MHC class I-restricted epitopes, NP147–155, and NP50–57, respectively. In contrast to the effect of the proteasome inhibitors on NP147–155, processing and presentation of NP50–57 to CTL is reduced. A 90% reduction in proteasome activity, but a significant increase in activity of a specific large cytosolic protease, was seen in mouse cells adapted to grow in the presence of an irreversible proteasome inhibitor. Enhanced presentation of NP147–155 and normal presentation of NP50–57 were seen in adapted cells. NP147–155 presentation was prevented and NP50–57 presentation decreased in proteasome inhibitor-adapted cells treated with one of the inhibitors of the specific protease. Limiting expression of the specific protease by including small interfering RNAs in cell extracts did not decrease NP147–155 processing; intracellularly overexpressing the specific protease or any of four other proteases from transfected vectors did not change processing and presentation of either epitope. In vitro incubation of purified proteasome with a 19-mer containing NP147–155 in the presence of a proteasome inhibitor reduced cleavage at the major site but increased appearance of other cleavage products. The authors interpret their results to indicate that generation of NP147–155 in the presence of proteasome inhibitors occurs by a combination of residual proteasome activity and downstream protease(s).
NAD, NKT cells, and autoimmune hepatitis
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-galactosylceramide (-GalCer) as determined by release of liver enzymes and histology. Bone marrow chimeras showed that P2X7R expression on lymphoid, not parenchyma, cells was responsible for the liver injury. Although prior injection of NAD protected wild-type mice against Con A or -GalCer-induced hepatitis, injection of NAD 3 h after priming with Con A or -GalCer resulted in increased liver damage and higher IFN- and IL-4 serum levels compared with controls. Liver and spleen NKT cells from Con A- or -GalCer-primed mice expressed higher levels of IFN- and IL-4 than cells from unprimed animals; cytokine levels further increased in mice injected with NAD after priming. NKT cells from NAD injected mice produced little IFN- and IL-4 after culture with -GalCer. The authors propose a model in which NAD provides an inhibitory signal to naive NKT cells by ADP-ribosylation but activates primed NKT cells in autoimmune hepatitis. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
E)-7 Integrin-Positive Epithelial Dendritic Cell Population Expressing Langerin and Tight Junction Proteins
-Directed IgA Switching and Changes in B Cell Fate
T Cells in Response to Mycobacterium tuberculosis
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