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Lamina propria DCs
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intCD11blow and CD11chighCD8–CD11bhigh, respectively, in mouse small intestine by immunohistochemistry and flow cytometry. These two subsets were not found in mice deficient in PPs and isolated lymphoid follicles. Both subsets were phenotypically immature by morphology, histochemical staining, and expression of costimulatory molecules. CCR7 mRNA was highly expressed in both R1 and R2 cells. LP-DCs bound one CCL7 ligand (CCL19), reacted in situ with anti-CCL7 mAb, and migrated toward another CCL7 ligand (CCL21) in an optical chemotaxis assay system. R1 and R2 cells had high surface expression of 
7 integrin compared with two populations of PP-DCs with intermediate or low levels of expression. All LP-DCs and PP-DC subsets were detected in mesenteric lymph nodes (MLNs). The two LP-DC subsets were almost totally absent in MLNs of CCR7–/– mice and were greatly reduced in CCL19–/– mice expressing only a mutated CCL21; there were no reductions in the PP-DC subsets. MLN-DCs were CCR7+ and contained TUNEL+ cytoplasmic debris positive for alkaline phosphatase found in intestinal epithelial cells (IECs) but not in DCs. R1 cells took up more CFSE-labeled apoptotic IECs in vitro than R2 cells. OVA-loaded apoptotic IECs cocultured with LP-DCs induced OVA-specific T cells to proliferate and produce high levels of IL-4 and IL-10 in vitro. The authors propose that LP-DCs migrate to MLNs in a CCR7-dependent manner and present IEC-associated Ags to CD4+ T cells.
Cerebral malaria and TGF-1
Fatal cerebral malaria is characterized by accumulation of Plasmodium falciparum-parasitized RBC (PRBCs) in brain and high serum levels of TNF-. Regulation of TGF- release by platelets determines outcome of P. falciparum infection in mice. It is not known if the two cytokines act synergistically. Wassmer et al. (p. 1180
) found that TNF- stimulated human brain endothelial cells (HBECs) were more susceptible to apoptosis induced by platelets and bound significantly more platelets than resting HBECs. Platelet binding and endothelial apoptosis were reduced by addition of anti-CD41/61, anti-ICAM-1, or anti-CD40 mAb. No apoptosis was seen in resting HBECs treated with buffer, human rTGF-1, resting platelets, or thrombin-activated platelet supernatant. Highest levels of apoptosis were seen in TNF--stimulated HBECs treated with human rTGF-1, resting platelets, or thrombin-activated platelets. Addition of anti-human TGF-1 mAb to thrombin-activated platelet supernatant reduced apoptosis to the level seen with resting platelet supernatants. Supernatants of thrombin-activated platelets were as active in inducing HBEC apoptosis as supernatants from platelets activated by contact with PRBCs. The authors propose a sequence of events in cerebral malaria that involves binding and adhesion of parasite-activated platelets or PRBCs to TNF--primed endothelial cells followed by local TGF- release and endothelial cell apoptosis.
APC responses to polyoma virus
The Benjamin laboratory demonstrated differences in cytokine response to polyoma (Py) virus infection in two strains of mice. Mice of a resistant strain mount a Th1 response with high levels of IL-12 and remain tumor free, whereas mice of a susceptible strain produce IL-10 in a Th2 response and develop tumors. Susceptibility is dominant in F1 progeny of a cross between the two strains. The same laboratory (Velupillai et al. (p. 1148 )) showed that purified B cells or macrophages from susceptible or F1 mice were the major IL-10 responders but that purified B cells or dendritic cells (DCs) from resistant mice were the major IL-12 responders. All cells responded to complete Py virus or virus-like particles (VLPs), except that macrophages from susceptible or F1 animals responded only to complete virus. The response of peritoneal exudate cells to VLPs was limited to purified B cells from susceptible or F1 mice and to purified macrophages from resistant mice. The responding cells exhibited a 2-fold induction of MHC class II molecules. Neuraminidase pretreatment of APCs blocked the cytokine response to virus or VLPs. Higher levels of TLR4 were detected in B cells from susceptible and F1 mice, and pretreatment with anti-TLR4 prevented VLP-induced production of IL-10 by splenocytes. TLR2 was detected at higher levels on macrophages and DCs from resistant mice, and pretreatment of splenocytes partially inhibited the VLP-induced IL-12 response. The authors show that the cytokine response of naive APCs from mice susceptible or resistant to Py virus infection is mediated by intact virus or VLPs binding TLR4 or TLR2, respectively, plus virus-sialic acid interactions.
Ret finger protein
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gene following viral infection is accomplished by an enhanceosome comprised of several transcription factors. Both canonical and noncanonical I
B kinase (IKK) family members phosphorylate components of the enhanceosome by an undetermined mechanism. Zha et al. (p. 1072
) isolated cDNAs encoding Ret finger protein (RFP) from a human B cell library using full-length IKK
as bait in yeast two-hybrid screens. RFP coprecipitated with IKK, , , or TBK1 (TANK-binding kinase-1) from mouse cells cotransfected with hemagglutinin-tagged RFP plus one of the other Flag-tagged expression plasmids. Immunofluorescence showed transfected RFP colocalized with IKK primarily in the cytoplasm. Endogenous RFP associated with endogenous IKK only in cells treated with poly(I:C). RFP was phosphorylated strongly by IKK and TBK1 but only weakly by IKK or IKK in in vitro kinase assays. RFP inhibited activation of NF-B by IKKs, TBK1, TNF, or IL-1; RFP also inhibited TBK1 and IKKactivation of IFN-stimulated response element (ISRE). The inhibitory activity was mapped to the C-terminal RFP domain using deletion mutants. RFP RNA interference reduced expression levels of transfected and endogenous RFP and enhanced TLR3-induced NF-B activation and ISRE-dependent transcription in TLR3-transfected cells. Coprecipitation experiments indicated that RFP coprecipitated with IFN regulatory factor-3 (IRF-3) but did not compete with either its phosphorylation by IKK or its dimerization. IKK-mediated translocation of IRF-3 into the nucleus of doubly transfected cells was blocked by addition of RFP. The authors propose that RFP sequesters IKK and IRF-3 in the cytoplasm, thereby preventing ISRE and NF-B activation by IKK family members in an antiviral response. Early preplasma cell checkpoint
Interaction of Ags with B cells results in differentiation of short-lived and long-lived plasma cells (PCs). B lymphocyte-induced maturation protein-1 (Blimp-1) largely controls progression from B cell activation to late stages of PC differentiation. Culton et al. (p. 790 ) found a distinct population of pre-PCs with a surface phenotype of CD138int CD19 B220 in spleens of wild-type mice and mice transgenic (Tg) for an anti-Smith (Sm) H chain rearrangement. Anti-Sm B cells from spleens and bone marrow of normal, anti-Sm Tg, and lupus-prone mice were enriched among CD138int vs CD138– cells, and a significant fraction of the CD138int cells were autoreactive. CD138int cells were found primarily in spleen follicles near the T cell-rich border. Some non-Sm, but no anti-Sm, CD138int cells in non-Tg and anti-Sm Tg mice became Ab-secreting cells (ASCs). Frequency of anti-Sm ASCs among CD138int B cells was higher than among anti-Sm CD138– B cells in anti-Sm Tg lupus-prone mice and differentiated to CD138high stages. Anti-Sm CD138int cells from nonautoimmune mice incorporated BrdU more rapidly and had accelerated apoptosis compared with non-Sm CD138int cells; neither cell type entered into the cell cycle. Anti-Sm CD138int cells in lupus-prone mice underwent apoptosis or differentiated to CD138high and PC stages. Blimp-1 mRNA was elevated in non-Sm CD138int vs CD138– cells, but not in anti-Sm CD138int cells, of nonautoimmune mice. Blimp-1 mRNA levels were highest in anti-Sm CD138int B and anti-Sm CD138high pre-PCs of lupus-prone mice. Up-regulation of mRNA for one B lymphocyte stimulator receptor correlated with anti-Sm CD138int B cell differentiation to ASCs. The data describe an early short-lived pre-PC population of B cells whose differentiation is Ag-driven in bone marrow and spleen of normal mice. This checkpoint for regulation of autoreactive B cells is absent in lupus-prone mice.
ERK1/2 and colitis
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B p50/p105 limits expression of IL-12 p40 and prevents H. hepaticus-induced lower bowel inflammation. Yet the pathway from TLR2 activation by H. hepaticus and IL-12 p40 expression is not clearly defined. Tomczak et al. (p. 1244
) from the same laboratory saw rapid phosphorylation of ERK1/2 and MEK1/2 in bone marrow-derived macrophages (BMDMs) from wild-type mice challenged with live bacteria. Phosphorylation was prevented, and higher levels of IL-12 p40 mRNA and secreted IL-12 p40 and p70 protein were seen in bacteria-stimulated wild-type BMDMs treated with a selective inhibitor of ERK1/2 activation and in BMDMs from mice deficient for p50/p105 or tumor progression locus-2 (Tpl-2) kinase. Although no changes in phosphorylation were seen in H. hepaticus-stimulated BMDMs from IL-10–/– mice, IL-12 p40 mRNA levels were lower than controls; IL-12 p40 expression in the IL-10–/– cells was enhanced by addition of exogenous IL-10 plus the ERK1/2 inhibitor compared with mock-treated IL-10–/– controls. Induction of c-Fos was inhibited in H. hepaticus-stimulated wild-type BMDMs treated with the ERK1/2 inhibitor or in BMDMs deficient for p50/p105 or Tpl-2 but not for IL-10. Bacteria induced lower levels of IL-12 p40 in c-Rel-deficient BMDMs vs wild-type controls, but the levels increased in the presence of the ERK1/2 inhibitor. The authors propose a model by which H. hepaticus interaction with TLR2 induces ERK activation by a pathway dependent upon Tpl-2 and p105. ERK-induced c-Fos inhibits IL-12 p40 expression. Peripheral B cell tolerance
Studies of B cell tolerance have focused on early stages of tolerance. However, induction of peripheral B cell tolerance to Abs expressed at low levels or not at all in the bone marrow has not been described. Aït-Azzouzene et al. (p. 939
) compared B cell numbers and phenotypes in lymphoid organs of mice ubiquitously expressing a membrane tethered Ig-reactive single chain Ab at a very low level (pUIiklow) or at a higher level (pUlikhigh). Whereas pUIiklow transgenic mice had no recirculating B220high/Ig+ B cells and levels of B220int/Ig+ cells in bone marrow were similar to nontransgenic controls, they had significant, but reduced, numbers of Ig+ B cells in spleen and lymph nodes. No Ig+ B cells were detected in the periphery of pUlikhigh mice, and sIg was internalized in their bone marrow cells. Only pUlikhigh mice had significant elevation of peripheral and newly formed 
+ cells and DNA recombination products in splenic sIg+ B cells. Peripheral cells in pUIiklow mice had surface markers characteristic of immature cells; mice lacked Ig+ cells in the marginal zone but had significant numbers of peritoneal cavity sIg+ B-1a cells. BrdU labeling studies indicated high Ig+ B cell turnover in the spleen, but not the peritoneal cavity, of pUIiklow mice compared with nontransgenic mice. Reduced numbers of Ig+ B cells were detected in spleen and lymph nodes, but not in bone marrow, of pUIiklow recipients of wild-type bone marrow; only Ig+ B cells were detected in peripheral organs of pUlikhigh recipients. Reduced serum IgM,, but no IgA, or IgG,, was detected in pUIiklow mice, whereas no serum Ig of any kind was found in pUlikhigh mice. The experiments suggest that tolerance-induced peripheral B cell deletion occurs in pUIiklow mice having a low level of expression of macroself Ag in the bone marrow, but central tolerance and receptor editing predominate in pUlikhigh mice.
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
B Kinase Family Members
1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria
B Is Responsible for Elevated Expression of IL-12 p40 Observed after Challenge with Helicobacter hepaticus
-Reactive Ligand
This article has been cited by other articles:
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  D. A. Hume Comment on "CCR7 Is Critically Important for Migration of Dendritic Cells in Intestinal Lamina Propria to Mesenteric Lymph Nodes" J. Immunol., August 15, 2006; 177(4): 2035 - 2035. [Full Text] [PDF]
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