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Primary neonatal T cell responses comprise both T helper (Th) cell subsets, but Th1 cells express high levels of interleukin 13 receptor alpha1 (IL-13R alpha 1), which heterodimerizes with IL-4R alpha. During secondary antigen challenge, Th2-produced IL-4 triggers the apoptosis of Th1 cells via IL-4R alpha/IL-13R alpha 1, thus explaining the Th2 bias in neonates. We show that neonates acquire the ability to overcome the Th2 bias and generate Th1 responses starting 6 d after birth. This transition was caused by the developmental maturation of CD8 alpha(+)CD4(-) dendritic cells (DCs), which were minimal in number during the first few days of birth and produced low levels of IL-12. This lack of IL-12 sustained the expression of IL-13R alpha 1 on Th1 cells. By day 6 after birth, however, a significant number of CD8 alpha(+)CD4(-) DCs accumulated in the spleen and produced IL-12, which triggered the down-regulation of IL-13R alpha 1 expression on Th1 cells, thus protecting them against IL-4-driven apoptosis.

The chemopreventive and chemoprotective activities of green tea have been attributed to the polyphenolic ingredient (-)-epigallocatechin-3-gallate (EGCG). Here, we report that treatment of human breast epithelial (MCF10A) cells with EGCG induces the expression of glutamate-cysteine ligase, manganese superoxide dismutase (MnSOD), and heme oxygenase-1 (HO-1). NF-E2-related factor (Nrf2) has been reported to regulate the antioxidant response element (ARE)-mediated expression of many antioxidant as well as detoxifying enzymes. The nuclear accumulation, ARE binding and transcriptional activity of Nrf2 were increased by EGCG treatment. Silencing of Nrf2 by siRNA gene knockdown rendered the MCF10A cells less sensitive to the EGCG-induced expression of HO-1 and MnSOD. Furthermore, EGCG activated Akt and extracellular signal-regulated protein kinase1/2 (ERK1/2). The pharmacologic inhibition of these kinases abrogated the nuclear translocation of Nrf2 induced by EGCG. These findings suggest that Nrf2 mediates EGCG-induced expression of some representative antioxidant enzymes, possibly via Akt and ERK1/2 signaling, which may provide the cells with acquired antioxidant defense capacity to survive the oxidative stress.

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon gamma (IFNgamma) protect against passive TID. Because IFNgamma is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and beta-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNgamma that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNgamma led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNgamma induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17-producing cells.

Currently, transition of T cells from effector to memory is believed to occur as a consequence of exposure to residual suboptimal Ag found in lymphoid tissues at the waning end of the effector phase and microbial clearance. This led to the interpretation that memory arises from slightly activated late effectors producing reduced amounts of IFN-gamma. In this study, we show that CD4 T cells from the early stage of the effector phase in which both the Ag and activation are optimal also transit to memory. Moreover, early effector T cells that have undergone four divisions expressed significant IL-7R, produced IFN-gamma, and yielded rapid and robust memory responses. Cells that divided three times that had marginal IL-7R expression and no IFN-gamma raised base level homeostatic memory, whereas those that have undergone only two divisions and produced IFN-gamma yielded conditioned memory despite low IL-7R expression. Thus, highly activated early effectors generated under short exposure to optimal Ag in vivo develop into memory, and such transition is dependent on a significant production of the cell's signature cytokine, IFN-gamma.

Background: Most patients with acute viral hepatitis A (AVHA) spontaneously recover, but a few patients experience complications. This study was carried out to examine clinical features of AVHA complicated with acute renal failure (ARF)., Method: Medical records of 404 patients with AVHA were reviewed. Clinical features of AVHA patients with ARF (group A) were compared with those of AVHA patients without ARF (group B)., Result: ARF complication was present in 11 patients (3%). There were no differences between group A and B in sex ratio and age. Microscopic hematuria (7 cases), proteinuria (7 cases), metabolic acidosis (4 cases), oliguria (4 cases), pulmonary edema (3 cases) and hyperkalemia (2 cases) were found in group A. The prevalence of heavy alcohol drinking (64% vs 3%, p<0.001) and diabetes mellitus (18% vs 1%, p=0.01) was higher in group A than B. The peak value of ALT (median: 4,290 IU/L vs 1,266 IU/L, p=0.006) and total bilirubin (median: 10.8 mg/dL vs 6.0 mg/dL, p=0.001) was higher in group A than B. Duration of admission was longer in group A than B (median: 14 days vs 5 days, p<0.001). Four patients of group A recovered with renal replacement therapy, while 7 patients recovered with conservative treatment., Conclusions: The AVHA patients with ARF experienced more severe hepatitis than those without ARF, but they had a good prognosis with the proper treatment.

Ig-proteolipid protein 1 (Ig-PLP1) is an Ig chimera expressing the encephalitogenic PLP1 peptide corresponding to amino acid residues 139-151 of PLP. Newborn mice given Ig-PLP1 in saline on the day of birth and challenged 7 wk later with PLP1 peptide in CFA develop an organ-specific neonatal immunity that confers resistance against experimental allergic encephalomyelitis. The T cell responses in these animals are comprised of Th2 cells in the lymph node and anergic Th1 lymphocytes in the spleen. Intriguingly, the anergic splenic T cells, although nonproliferative and unable to produce IFN-gamma or IL-4, secrete significant amounts of IL-2. Studies were performed to determine whether the two populations display any structural differences in the TCR H chain variable region that could contribute to the differential affinity and retention in different organs. Responsive Th2 lymph node T cells and anergic splenic lymphocytes were immortalized, and the structures of their TCR Vbeta were determined. The results show that Vbeta and Jbeta usage was random, but the CDR3 regions of the lymph node cells had a conserved Gly-Gly motif. Analysis of TCR affinity/avidity correlated the Gly-Gly motif with lower affinity and retention of the Th2 cells in the lymph node. Also, it is suggested that a higher TCR affinity may be a contributing factor for the development of the neonatal Th1 response in the spleen.

Harmful algal blooms, caused by rapid growth and accumulation of certain microalgae in the ocean, pose considerable impacts on marine environments, aquatic industries and even public health. Here, we present the 7.2-megabase genome of the marine bacterium Hahella chejuensis including genes responsible for the biosynthesis of a pigment which has the lytic activity against a red-tide dinoflagellate. H.chejuensis is the first sequenced species in the Oceanospiralles clade, and sequence analysis revealed its distant relationship to the Pseudomonas group. The genome was well equipped with genes for basic metabolic capabilities and contained a large number of genes involved in regulation or transport as well as with characteristics as a marine heterotroph. Sequence analysis also revealed a multitude of genes of functional equivalence or of possible foreign origin. Functions encoded in the genomic islands include biosynthesis of exopolysacchrides, toxins, polyketides or non-ribosomal peptides, iron utilization, motility, type III protein secretion and pigmentation. Molecular structure of the algicidal pigment, which was determined through LC-ESI-MS/MS and NMR analyses, indicated that it is prodigiosin. In conclusion, our work provides new insights into mitigating algal blooms in addition to genetic make-up, physiology, biotic interactions and biological roles in the community of a marine bacterium.

To date, very few Ag-based regimens have been defined that could expand T regulatory (Treg) cells to reverse autoimmunity. Additional understanding of Treg function with respect to specificity and broad suppression should help overcome these limitations. Ig-proteolipid protein (PLP)1, an Ig carrying a PLP1 peptide corresponding to amino acid residues 139-151 of PLP, displayed potent tolerogenic functions and proved effective against experimental allergic encephalomyelitis (EAE). In this study, we took advantage of the Ig-PLP1 system and the PLP1-specific TCR transgenic 5B6 mouse to define a regimen that could expand Ag-specific Treg cells in vivo and tested for effectiveness against autoimmunity involving diverse T cell specificities. The findings indicate that in vivo exposure to aggregated Ig-PLP1 drives PLP1-specific 5B6 TCR transgenic cells to evolve as Treg cells expressing CD25, CTLA-4, and Foxp3 and producing IL-10. These Treg cells were able to suppress PLP1 peptide-induced EAE in both SJL/J and F(1) (SJL/J x C57BL/6) mice. However, despite being effective against disease induced with a CNS homogenate, the Treg cells were unable to counter EAE induced by a myelin basic protein or a myelin oligodendrocyte glycoprotein peptide. Nevertheless, activation with Ag before transfer into the host mice supports suppression of both myelin oligodendrocyte glycoprotein- and myelin basic protein peptide-induced EAE. Thus, it is suggested that activation of Treg cells by the cognate autoantigen is necessary for operation of broad suppressive functions.

IL-10, a powerful anti-Th1 cytokine, has shown paradoxical effects against diabetes. The mechanism underlying such variable function remains largely undefined. An approach for controlled mobilization of endogenous IL-10 was applied to the NOD mouse and indicated that IL-10 encounter with diabetogenic T cells within the islets sustains activation, while encounter occurring peripheral to the islets induces tolerance. Insulin beta-chain (INSbeta) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSbeta triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSbeta delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSbeta was unable to suppress the disease in 10-wk-old insulitis-positive animals whose diabetogenic T cells have populated the islets. This is not due to irreversibility of the disease because soluble Ig-INSbeta did delay diabetes in these older mice. Evidence is provided indicating that upon migration to the islet, T cells were activated and up-regulated CTLA-4 expression. IL-10, however, reverses such up-regulation, abolishing CTLA-4-inhibitory functions and sustaining activation of the islet T lymphocytes. Therefore, IL-10 supports T cell tolerance in the periphery, but its interplay with CTLA-4 sustains activation within the islets. As a result, IL-10 displays opposite functions against diabetes in young vs older insulitis-positive mice.

Autoimmunity presumably manifests as a consequence of a shortfall in the maintenance of peripheral tolerance by CD4(+)CD25(+) T regulatory cells (Tregs). However, the mechanism underlying the functional impairment of Tregs remains largely undefined. In this study a glutamic acid decarboxylase (GAD) diabetogenic epitope was expressed on an Ig to enhance tolerogenic function, and the resulting Ig-GAD expanded Tregs in both young and older insulitis-positive, nonobese diabetic (NOD) mice, but delayed autoimmune diabetes only in the former. Interestingly, Tregs induced at 4 wk of age had significant active membrane-bound TGF-beta (mTGF-beta) and sustained protection against diabetes, whereas Tregs expanded during insulitis had minimal mTGF-beta and could not protect against diabetes. The Tregs probably operate suppressive function through mTGF-beta, because Ab blockade of mTGF-beta nullifies protection against diabetes. Surprisingly, young Tregs that modulated pathogenic T cells maintained stable frequency over time in the protected animals, but decreased their mTGF-beta at the age of 8 wk. More strikingly, these 8-wk-old mTGF-beta-negative Tregs, which were previously protective, became unable to confer resistance against diabetes. Thus, a developmental decline in active mTGF-beta nullifies Treg function, leading to a break in tolerance and the onset of diabetes.

Primary neonatal Th1 cells develop alongside of Th2 upon priming of the newborn but undergo apoptosis upon recall with antigen. These Th1 cells were isolated, and their death was correlated with elevated IL-13Ralpha1 chain expression. Strikingly, neutralization of Th2s' IL-4 reduced apoptosis, sustained recall responses, and the live Th1 cells displayed a decrease in IL-13Ralpha1 expression. Blockade of IL-13Ralpha1 or IL-4Ralpha also restores recall and secondary Th1 responses. Adult T cells primed within the neonatal environment did not upregulate IL-13Ralpha1 chain or undergo apoptosis and developed recall Th1 responses. These observations indicate that developmental expression of IL-13Ralpha1 along with IL-4Ralpha provides a receptor through which IL-4 induces death of Th1 cells and skews neonatal immunity toward Th2.

Ig-PLP1 is an Ig chimera expressing proteolipid protein-1 (PLP1) peptide corresponding to aa residues 139-151 of PLP. Newborn mice given Ig-PLP1 in saline on the day of birth and challenged 7 wk later with PLP1 peptide in CFA develop an organ-specific neonatal immunity that confers resistance against experimental allergic encephalomyelitis. The T cell responses in these animals comprise Th2 cells in the lymph node and anergic Th1 lymphocytes in the spleen. Intriguingly, the anergic splenic T cells, although nonproliferative and unable to produce IFN-gamma or IL-4, secrete significant amounts of IL-2. In this work, studies were performed to determine whether costimulation through B7 molecules plays any role in the unusual form of splenic Th1 anergy. The results show that engagement of either B7.1 or B7.2 with anti-B7 Abs during induction of EAE in adult mice that were neonatally tolerized with Ig-PLP1 restores and exacerbates disease severity. At the cellular level, the anergic splenic T cells regain the ability to proliferate and produce IFN-gamma when stimulated with Ag in the presence of either anti-B7.1 or anti-B7.2 Ab. However, such restoration was abolished when both B7.1 and B7.2 molecules were engaged simultaneously, indicating that costimulation is necessary for reactivation. Surprisingly, both anti-B7.1 and anti-B7.2 Abs triggered splenic dendritic cells to produce IL-12, a key cytokine required for restoration of the anergic T cells. Thus, recovery from neonatally induced T cell anergy requires B7 molecules to serve double functions, namely, costimulation and induction of cytokine production by APCs.