Organ specific modulation of autoreactive T cells by neonatal exposure to antigens

During T cell development within the thymus the immune system has developed several regulatory checkpoints to ensure the elimination of T cells endowed with antigen receptors specific for self antigens. Although such a tight regulation exists, some autoreactive T cells escape and undergo the maturation process. The activation of those autoreactive T cells leads to the development of autoimmune diseases. The neonatal period has been considered as a window during which the encounter with antigens instructs not to develop immune responses, but rather, induces tolerance. Therefore, introduction with defined autoantigens into neonates could be an attractive strategy to induce neonatal tolerance, preventing the development of autoimmunity. The necessity of incomplete Freund\u27s adjuvant (IFA), however, hampers its clinical application. It has been shown that immunoglobulin (Ig) can be used as an antigenic delivery system, and such delivery was efficient by increasing peptide presentation by 100-1000 fold. Furthermore, Igs are persistent for a long time in vivo. Herein, we hypothesized that Ig-mediated peptide delivery into neonates may replace the requirement of IFA, thereby inducing neonatal tolerance. Following the introductory literature overview, part II describes the expression of a dominant encephalitogenic peptide (PLP 139-151, PLP1) derived from proteolipid protein (PLP) in place of CDR3 region of Ig molecule. PLP is a known autoantigen for experimental allergic encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS). The results indicate that the peptide was incorporated into the variable region in a correct reading frame. Furthermore, peptide presentation by chimeric Ig molecule was antigen specific and had great efficiency in T cell stimulation by 100-1000 fold. In the following part III it was shown that neonatal injection with resulting Ig- PLP1 conferred a resistance to EAE without the presence of IFAThe mechanism underlying such resistance included IL-4-driven lymph node deviation, and IFNYγdependent splenic anergy restorable by exogenous IFNγ or IL-12. Part IV showed that neonatal tolerance induced by Ig-PLP1 was unique and differentially regulated by the dose of antigen, the presence of adjuvant, and the number of injectionsThe results indicate that the dose of Ig-PLP1 displayed a quantitative variation in the outcome of tolerance, whereas adjuvant and the number of injections had a rather qualitative effect on the neonatal tolerance. Part V demonstrated the cellular mechanism for splenic T cell anergyThe results show that splenic cells from Ig-PLP1 tolerized mice displayed an anergic phenotype by the inability to upregulate IL-2 receptor a chain (CD25), which is responsible for responsiveness to IL-2. Furthermore, this defect in CD25 expression by splenic cells was shown to be critical in order to maintain long-lasting persistence of Ig-PLP1 mediated tolerance

Nonredundant Roles for CD1d-restricted Natural Killer T Cells and Conventional CD4+ T Cells in the Induction of Immunoglobulin E Antibodies in Response to Interleukin 18 Treatment of Mice

Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4+ T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d−/− mice that lack natural killer T (NKT) cells and in class II−/− mice that lack conventional CD4+ T cells. However, class II−/− mice reconstituted with conventional CD4+ T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)α chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4+ T cells express low levels of IL-18Rα and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4+ T cells are essential for B cell IgE responses after the administration of IL-18. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4+ T cells demonstrate their helper function in the presence of NKT cells

Basophils Produce IL-4 and Accumulate in Tissues after Infection with a Th2-inducing Parasite

Using mice in which the eGfp gene replaced the first exon of the Il4 gene (G4 mice), we examined production of interleukin (IL)-4 during infection by the intestinal nematode Nippostrongylus brasiliensis (Nb). Nb infection induced green fluorescent protein (GFP)pos cells that were FcɛRIpos, CD49bbright, c-kitneg, and Gr1neg. These cells had lobulated nuclei and granules characteristic of basophils. They were found mainly in the liver and lung, to a lesser degree in the spleen, but not in the lymph nodes. Although some liver basophils from naive mice express GFP, Nb infection enhanced GFP expression and increased the number of tissue basophils. Similar basophil GFP expression was found in infected Stat6−/− mice. Basophils did not increase in number in infected Rag2−/− mice; Rag2−/− mice reconstituted with CD4 T cells allowed significant basophil accumulation, indicating that CD4 T cells can direct both tissue migration of basophils and enhanced IL-4 production. IL-4 production was immunoglobulin independent and only partially dependent on IL-3. Thus, infection with a parasite that induces a “Th2-type response” resulted in accumulation of tissue basophils, and these cells, stimulated by a non-FcR cross-linking mechanism, are a principal source of in vivo IL-4 production

Sustainable bioelectrochemical systems for bioenergy generation via waste treatment from petroleum industries

Petroleum industries are large water consumers and generate a lot of wastewater at various stages of industrial operations. Wastewater from the petroleum industries contain recalcitrant pollutants such as hydrocarbons that are present in high concentrations, dissolved solids and sulfur compounds that can pose potential environmental threat. Bioelectrochemical systems (BESs) are known to be sustainable processes to treat the various kinds of wastewaters such as petroleum wastewater, while simultaneously generating the bioelectricity and value-added chemicals. This review focuses on various applications of BESs such as microbial fuel cells (MFC), microbial electrolysis cells (MEC), and microbial desalination cells (MDC) using diverse types of wastewaters (petroleum sludge, produced water, formation water, and petroleum refinery wastewater) from the petroleum industries. Overall, a hybrid type BES with hydrocarbon wastewater achieved a 98% of columbic efficiency, 96.5% of chemical oxygen demand (COD), 99% of phenanthrene, 94% of pyrene and 80% of TDS removal which are superior to single and dual chamber BES performances. The review also compares the existing biological processes with BESs in terms of the treatment of hydrocarbons and process sustainability. Treatment efficiency of petroleum wastes via the BES can be further improved by integrating the biological and electrochemical processes to develop a sustainable approach to bio-refinery route

IL-4 Derived from Non-T Cells Induces Basophil- and IL-3-independent Th2 Immune Responses

How Th2 immunity develops in vivo remains obscure. Basophils have been considered key innate cells producing IL-4, a cytokine essential for Th2 immunity. Increasing evidence suggests that basophils are dispensable for the initiation of Th2 immunity. In this study, we revisited the role of basophils in Th2 immune responses induced by various types of adjuvants. Mice deficient in IL-3 or IL-3 receptor, in which basophil lymph node recruitment is completely abolished, fully developed wild type level Th2 CD4 T cell responses in response to parasite antigen or papain immunization. Similar finding was also observed in mice where basophils are inducibly ablated. Interestingly, IL-4-derived from non-T cells appeared to be critical for the generation of IL-4-producing CD4 T cells. Other Th2 promoting factors including IL-25 and thymic stromal lymphopoietin (TSLP) were dispensable. Therefore, our results suggest that IL-3- and basophil-independent in vivo Th2 immunity develops with the help of non-T cell-derived IL-4, offering an additional mechanism by which Th2 type immune responses arise in vivo.Sohee Kim, Hajime Karasuyama, Angel F. Lopez, Wenjun Ouyang, Xiaoxia Li, Graham Le Gros, and Booki Mi

Spontaneous T Cell Proliferation: A Physiologic Process to Create and Maintain Homeostatic Balance and Diversity of the Immune System

Naive T lymphocytes undergo heterogeneous proliferative responses when introduced into lymphopenic hosts, referred to as “homeostatic proliferation” and “spontaneous proliferation.” Spontaneous proliferation is a unique process through which the immune system generates memory phenotype cells with increasing T cell receptors repertoire complexity. Here, the mechanisms that initiate and control spontaneous proliferation are discussed