IL-33-mediated protection against experimental cerebral malaria is linked to induction of Type 2 innate lymphoid cells, M2 macrophages and regulatory T cells

Author Summary Cerebral malaria (CM) caused by the parasite Plasmodium sp . is a fatal disease, especially in children. Currently there is no effective treatment. We report here our investigation on the role of a recently discovered cytokine IL-33, in treating experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. IL-33 protects the mice against ECM. The protection is accompanied by a reduction of Th1 response and the enhancement of type 2 cytokine response. We also found that IL-33 mediates its protective effect by inducing a population of type 2 innate lymphoid cells (ILC2), which then polarize macrophages to alternatively-activated phenotypes (M2). M2 in turn expand regulatory T cells (Tregs) which suppress the deleterious Th1 response. Our report therefore reveals hitherto unrecognised mechanisms of the regulation of ECM and provide a novel function of IL-33

IL-15 induces type 1 and type 2 CD4(+) and CD8(+) T cells proliferation but is unable to drive cytokine production in the absence of TCR activation or IL-12/IL-4 simulation in vitro

Interleukin 15 (IL-15) is a pleiotropic cytokine produced principally by monocytes and affects both innate and acquired immunity. It has been shown that IL-15 is essential for the proliferation and maintenance of CD8+ memory cells but has little or no effect on naive CD8+ cells or CD4+ T cells. We report here, using an in vitro culture system of antigen-specific OVA TCR transgenic T cells as well as normal mouse T cell activated with anti-CD3 antibody that IL- 15, at high concentrations, induced proliferation of both naive and memory CD4+ and CD8+ cells. IL-15 also enhanced the differentiation of type 1 (IFN- + -producing) and type 2 (IL-5- producing) CD4+ and CD8+ T cells under IL-12 and IL-4 driving conditions, respectively. However, IL-15 alone was not efficient in stimulating cytokine production of these cells in the absence of T cell subset driving cytokines (IL-12 or IL-4) and/or simultaneous TCR activation. Together, these results demonstrate that IL-15, at high dose, is a pan-T cell growth factor. The apparent requirement of IL-15 for the maintenance of memory CD8+ cell in vivo may reflect the exceptionally restricted nature of this subpopulation of cells for IL-15. The inability of IL-15 alone to stimulate cytokine synthesis also suggests that IL-15 on its own does not drive antigen-specific T cells to exhaustion. The levels of these cells are maintained by IL-15 and they are only mobilized to carry out effector functions when subsequently confronted with specific pathogens

Effects of nitric oxide on the induction and differentiation of Th1 cells

We have previously shown that mice lacking inducible NO synthase are markedly more susceptible to Leishmania major infection but developed a significantly enhanced Th1 cell response compared with wild-type mice. Furthermore, at high concentrations, NO inhibited IL-12 synthesis by activated macrophages, thereby indirectly suppressing the expansion of Th1 cells. We report here that at low concentrations, NO selectively enhanced the induction of Th1 cells and had no effect on Th2 cells. NO exerted this effect in synergy with IL-12 during Th1 cell differentiation and had no effect on fully committed Th1 cells. NO appears to affect CD4+ T cells directly and not at the antigen-presenting cells. These results therefore provide an additional pathway by which NO modulates the immune response and contributes to the homeostasis of the immune system

IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population

Patients who survive sepsis can develop long-term immune dysfunction, with expansion of the regulatory T (Treg) cell population. However, how Treg cells proliferate in these patients is not clear. Here we show that IL-33 has a major function in the induction of this immunosuppression. Mice deficient in ST2 (IL-33R) develop attenuated immunosuppression in cases that survive sepsis, whereas treatment of naive wild-type mice with IL-33 induces immunosuppression. IL-33, released during tissue injury in sepsis, activates type 2 innate lymphoid cells, which promote polarization of M2 macrophages, thereby enhancing expansion of the Treg cell population via IL-10. Moreover, sepsis-surviving patients have more Treg cells, IL-33 and IL-10 in their peripheral blood. Our study suggests that targeting IL-33 may be an effective treatment for sepsis-induced immunosuppression

Geografia comunitária e educação de jovens e adultos : os educadores flâneurs sem terra do Assentamento Paulo César Vinha – Conceição da Barra/ES

O ano de 2015 é um marco histórico dos 30 anos do fim da Ditadura Militar no Brasil. Comemoram-se também os 30 anos do Movimento dos Trabalhadores Rurais Sem Terra (MST) no Estado do Espírito Santo. Nesse contexto, o presente estudo tem como objetivo problematizar as conexões entre as experiências geográficas de formação de educadores de jovens e adultos sem terra do Assentamento Paulo César Vinha, vividas com os territórios do campo, da “roça”, da “rua” e da cidade, e suas práxis nos territórios da Reforma Agrária. Tendo como referência as categorias de Experiência, Narrativa, Memória, Lembrança Encobridora e Práxis, nas perspectivas de Walter Benjamin, Sánchez Vázquez, Paulo Freire, Milton Santos, Edward Thompson, Eric Dardel, Sigmund Freud, entre outros, a pesquisa foi realizada com oito educadores sem terra que atuam na Modalidade da Educação de Jovens e Adultos (EJA) da Escola Córrego do Cedro, no Assentamento Paulo César Vinha, que possui vinculação com o MST e está localizado no município de Conceição da Barra, Território Norte do Espírito Santo. Para tanto, o estudo se beneficiou da Observação Participante, na perspectiva dialético-materialista. No processo investigativo, constatou-se que as experiências geográficas de alienação, de negação, de inconformismo e de idealização dos educadores sem terra são unificadas e transformadas nas práxis do MST, configurando-se como experiências geográficas das práxis nas perspectivas de recriar e (re)experienciar as Geografias Comunitárias Camponesas Sem Terra habitacional, econômica, educacional, religiosa, do lazer e da saúde. Dessa forma, os educadores transformam a si mesmos nessa experiência geográfica inconformista de recriação das geografias alienadas, perdidas ou idealizadas. A pesquisa apontou também para a possibilidade de superação das concepções e práticas restritas de formação inicial e formação continuada na Educação de Jovens e Adultos do campo e da cidade, por meio da constituição da formação comunitária, que não apenas considera e valoriza as experiências de educadores, mas que também concebe a sua transformação nas práxis, voltando-se para o atendimento aos anseios, demandas e interesses dos sujeitos da EJA na ótica da Educação Popular.L'année 2015 est un point de repère du 30e anniversaire de la fin de la Dictature Militaire au Brésil. Ils célèbrent aussi le 30e anniversaire du Mouvement des Travailleurs Ruraux Sans Terre (MST) dans l'État de L´Espírito Santo. Dans ce contexte, l'objectif de la présente recherche consiste à problématiser les connexions entre les expériences géographiques de la formation des éducateurs de jeunes et des adultes sans terre de l´Assentamento Paulo César Vinha, qu' ont été vécues avec des territoires du champ, la “ferme”, la “rue” et ville, et sa praxis dans les territoires de la réforme agraire. Parmi les catégories d'expérience, la narratif, la mémoire, le souvenir écran et la Praxis, les perspectives de Walter Benjamin, Sánchez Vázquez, Paulo Freire, Milton Santos, Edward Thompson, Eric Dardel, Sigmund Freud, entre autres, la recherche a été menée avec huit éducateurs sans terre qui travaillent dans la L´Éducation des Jeunes et des Adultes (EJA) de l´école Córrego do Cedro, dans la Communauté de l´Assentamento Paulo César Vinha, qui est lié avec le MST et est située dans la municipalité de Conceição da Barra, Territoire Nord du Espírito Santo. Par conséquent, l'étude a bénéficié de l'observation participante, dans la perspective dialectique matérialiste. Dans le processus d'enquête, il a été constaté que les expériences collectives géographiques de l'aliénation, déni, de non-conformité et de l'idéalisation des éducateurs sans terre sont unifiés et transformé dans les práxis du MST, devenant comme des expériences géographiques de la praxis des points de vue de (re)créer et (re)découvrir les Géographies Paysan Communautaires Sans Terre de l´habitation, économique, éducatif, religieuse, les loisirs et la santé; ainsi, les éducateurs se transforment. La recherche a également souligné la possibilité de surmonter les conceptions et pratiques de formation initiale limitées de la formation continue pour l´Éducation des Jeunes et des Adultes dans la campagne et la ville, à travers le renforcement de la formation de la communauté qui non seulement examine et évalue les expériences des éducateurs, mais qui conçoit sa transformation dans la praxis, se tournant pour répondre aux souhaits et les intérêts des sujets de l´Éducation des Jeunes et des Adultes dans la perspective de l'éducation populaire

Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice

IL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (−/−) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/−) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18−/− mice are uniformly susceptible. The infected IL-18−/− mice produced significantly lower levels of IFN-γ and larger amounts of IL-4 compared with similarly infected +/− and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18−/− mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-γ and TNF-α synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory cytokines, and therefore could be an important target for therapeutic intervention

The sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo

IL-15 is a pleiotropic cytokine that plays important roles in both innate and adaptive immunity. It is associated with a range of immunopathology, including rheumatoid arthritis and allograft rejection. IL-15 functions through the trimeric IL-15R complex, which consists of a high affinity binding a-chain and the common IL-2R b- and g-chains. Characterization of IL-15/IL-15R interactions may facilitate the development of improved IL-15 antagonists for therapeutic interventions. We previously constructed soluble murine IL-15Ra (sIL-15Ra) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15Ra, we have now constructed various truncated versions of sIL-15Ra. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15Ra. Sushi domains, common motifs in protein-protein interactions, contain four cysteines forming two disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of the first or fourth cysteine in sIL-15Ra completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15Ra to neutralize IL-15- induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15Ra lost its ability to inhibit carrageenan-induced local inflammation and allogenic cell-induced T cell proliferation and cytokine production in vivo. Thus, the Sushi domain is critical for the functional activity of sIL-15Ra