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The Cervical Thymus
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50% of BALB/c and 33% of C57BL/6 mice by histological and immunohistochemical analyses on serial sections of cervical tissue blocks. Thymus tissue also was detected in two of three human parathyroid tissue samples. Cervical thymi had discrete cortical and medullary compartments and expressed Foxn1 and pre-T
mRNAs. Relative sizes of double-negative and single- and double-positive thymocyte populations were similar in thoracic and cervical thymi. Thymocytes from either thymus were activated by anti-CD28 or anti-CD3 Abs. Transgenic strains of mice demonstrated both positive and negative selection in their cervical thymi, and CD4+ T cells expressing a Foxp3 transgene were restricted to the medullary compartment of the cervical thymus. Cervical thymus tissue grafted under the kidney capsule of nude mice exported T cells to the periphery. The spectrum of tissue-restricted Ags expressed by both thymi was similar, but the heterogeneity of expression levels for individual Ags was greater among cervical thymic samples. The authors conclude that cervical thymic tissue functionally resembles the thoracic thymus and caution that an ectopic thymus may project a different range of self-Ags. Tregs in Stem Cell Treatment for MM
Patients with multiple myeloma (MM) have increased remission rates and survival times after combination therapy that includes high-dose chemotherapy plus autologous stem cell transplantation. Hemopoietic stem cells are mobilized with cyclophosphamide (Cy), followed by administration of G-CSF to stimulate them. However, neither the phenotype nor function of the mobilized T cells collected by leukapheresis after treatment has been determined. Condomines et al. (p. 6631 ) found a decrease in overall T cells, CD3+ T cells, and NK cells 6 days after treatment of 14 MM patients with Cy (day 0), including five daily G-CSF injections; T cell numbers recovered slowly through day 10 post-Cy treatment. Percentages of central memory, effector memory, and late effector CD4+ T cells remained constant throughout the treatment, and CD8+ T cell subset proportions were similar to those of healthy donors; there was a slight decrease in naïve CD4+ T cells. In contrast, percentages of CD25-expressing CD4+ and CD8+ T cells increased throughout the Cy/G-CSF treatment compared with pretreatment values. Leukapheresed CD25+ T cells expressing high levels of Foxp3, CTLA-4, and GITR (glucocorticoid-induced TNFR) mRNA and protein inhibited the in vitro activation of autologous CD4+CD25– T cells by allogeneic dendritic cells. The authors suggest that G-CSF is responsible for the increased frequency of regulatory T cells, following the Cy/G-CSF mobilization regimen, to collect autologous hemopoietic stem cells for treatment of patients with MM.
Uterine Antimicrobial Defenses
One goal of the endometrium is to protect the fetus from microbial infection. Stimulation of antimicrobial 
-defensins by uterine epithelial cells is dependent on IL-1 derived from another cell type, most likely macrophages. However, there are few details regarding macrophage/epithelial cell interactions within the human endometrium. Pioli et al. (p. 6647
) detected activation of caspase 1 and IL-1 in human peripheral blood monocytes and primary uterine macrophages stimulated with LPS. Supernatants from the stimulated macrophages induced a high level of human -defensin 2 (HBD2) production by polarized human uterine epithelial cells; HBD2 production was suppressed by the addition of anti-IL-1 mAb to the supernatants. Incubation of estrogen receptor-positive blood-derived monocytes with a high dose (100 nM) of estradiol for 24 h before LPS challenge increased IL-1 mRNA and protein production compared with controls; an estrogen receptor antagonist prevented the increase. The data show that LPS-stimulated production of IL-1 by macrophages induces HBD2 production by uterine epithelial cells in a system of macrophage/epithelial cell communication aimed at protecting the fetus against pathogenic challenge. A high dose of estradiol enhances the IL-1 production.
Fc
R1 Stability
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RI expression on the surface of mast cells and basophils. Fc
RIIIA, a variant found in humans, shares - and -chains with FcRI but has a different -chain. This variant receptor is stable in the absence of IgE, suggesting that the -chain is responsible for the difference in stability. Kubota et al. (p. 7008
) transfected mouse fibroblasts with human - and -chains to form an 2-type FcRI capable of binding IgE. The receptor was reduced by 90% in cells treated with brefeldin A, an inhibitor of protein transport to the cell surface; the reduction was not seen in transfectants preincubated with IgE. Brefeldin A did not decrease the expression level of a human 2-type FcRIIIA reconstituted in mouse cells. A panel of chimeras, in which portions of the non-IgE-binding region of the human FcRI -chain were replaced with the corresponding regions from FcRIIIA -chain, determined that the -chain stalk region conferred instability to FcRI. Deletion of 7 aas from the stalk region of the FcRIIIA -chain rendered the receptor as susceptible to brefeldin A down-regulation as wild-type FcRI. Conversely, insertion of three to seven alanines into the amino terminus of the stalk region of the FcRI -chain rendered it resistant to IgE-mediated up-regulation or brefeldin A-induced down-regulation. The authors demonstrate that the length of the -chain stalk region determines the instability and IgE up-regulation of surface FcRI. Intracellular preBCR Signaling
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5, Golgi-modified wild-type and TGN heavy chains detected by immunoblotting were at highest levels compared with ER and lamp-1 heavy chains; only wild-type and TGN-targeted preBCRs induced CD2 or CD22, although both ER and TGN complexes appeared on the cell surface. The results show that preBCR signaling is not propagated in the ER, but that preBCRs in the TGN are as active and those in the lysosome are 50% as active as wild-type preBCR complexes. Extent of signaling did not correlate with preBCR surface expression but did correlate with the extent of heavy chain TGN modification. Tryptophan and Tolerance
Modulation of tryptophan metabolism by IDO is involved in down-regulating T cells and curbing harmful inflammatory responses. However, the effect of IDO on specific T cell subsets has not been detailed. Fallarino et al. (p. 6752
) found decreased TCR 
-chain (CD3) surface expression on CD8+, but not CD4+, T cells cultured with IDO+ dendritic cells (DCs); decreased expression did not occur in the presence of a specific IDO inhibitor. Similar results were obtained by treating CD8+ T cells with low concentrations of tryptophan plus three tryptophan catabolites. No change in CD3 expression occurred in CD8+ T cells from mice lacking the general control nonderepressing 2 (GCN2) stress-response kinase. Anti-CD3- or Con A-induced proliferation of treated CD8+ T cells did not occur in vitro, and their production of IFN- and IL-2 was impaired. In vivo down-regulation of CD3 was detected in autoreactive CD8+ T cells adoptively transferred with peptide-loaded IDO+ DCs into NOD-SCID mice. Increased expression of Foxp3 mRNA and other markers of regulatory T (Treg) cells was measured in treated CD4+CD25– T cells cultured with IDO+ DCs or with tryptophan plus its catabolites; the treated cells inhibited proliferation of responder CD4+CD25– T cells from naïve mice in the presence of anti-CD3 Ab and APCs. Anti-IL-10 plus anti-CTLA-4 Abs abrogated the suppressive abilities of the generated Tregs. Generation of Tregs by exposure of CD4+CD25– T cells to tryptophan plus its catabolites required GCN2 kinase and TGF-. In vitro-generated Tregs protected NOD-SCID mice from induction of diabetes by spleen cells from a diabetogenic donor; the IDO inhibitor eliminated the protection. The data indicate that IDO and GCN2 kinase are involved in down-regulating CD3 expression in mouse CD8+ T cells and in converting CD4+CD25– T cells to a Treg phenotype.
Retrocyclin-Resistant HIV-1
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-defensin that inhibits HIV-1 infection of human CD4+ T cells, was converted into a more potent antiviral compound, RC-101, by a single amino acid substitution. Although HIV-1 develops resistance to retrocyclins, the mechanism is unknown. Cole et al. (p. 6900
) found that higher concentrations of RC-101 peptide were required to inhibit later 5-day rounds of HIV-1 infection of human cells. Sequence analysis of virus isolates collected at days 25, 50, 75, and 100 revealed novel amino acid substitutions compared with the initial virus stock. By day 25 (round 5), two mutations were detected. One substituted positively charged lysine for negatively charged glutamic acid at residue 426 in the CD4 binding region of envelope glycoprotein 120 (gp120); the second substituted positively charged arginine for hydrophilic glutamine at residue 574 in the heptad repeat 1 motif (HR1) of gp41. Only the HR1 mutation conferred resistance to RC-101. At day 75 (round 15), a third mutation was detected in the presence of a higher dose of RC-101, namely cationic substitution of lysine for arginine at residue 634 in the HR2 motif of gp41. Virus with this third mutation was codependent on RC-101 for infectivity. All three mutations were retained through day 100 (round 20). Insertion of the three cationic mutations into an HIV-1 molecular clone by site-directed mutagenesis confirmed that all were required for escape from high-dose RC-101 inhibition of HIV-1 infection of cells. The experiments demonstrate that HIV-1 develops resistance to -defensin by specific mutations that decrease the negative charge of its envelope. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
Production by Human Uterine Macrophages Up-Regulates Uterine Epithelial Cell Expression of Human -Defensin 2
-Chain and Induce a Regulatory Phenotype in Naive T Cells
-Chains
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