L14. Immunomodulatory properties of apoptotic cells.

International audienc

サベナの帰郷 : マジュンガにおけるコモロ人虐殺事件の記憶と忘却

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Human Dendritic Cells Activated by TSLP and CD40L Induce Proallergic Cytotoxic T Cells

Human thymic stromal lymphopoietin (TSLP) is a novel epithelial cell–derived cytokine, which induces dendritic cell (DC)-mediated CD4+ T cell responses with a proallergic phenotype. Although the participation of CD8+ T cells in allergic inflammation is well documented, their functional properties as well as the pathways leading to their generation remain poorly understood. Here, we show that TSLP-activated CD11c+ DCs potently activate and expand naive CD8+ T cells, and induce their differentiation into interleukin (IL)-5 and IL-13–producing effectors exhibiting poor cytolytic activity. Additional CD40L triggering of TSLP-activated DCs induced CD8+ T cells with potent cytolytic activity, producing large amounts of interferon (IFN)-γ, while retaining their capacity to produce IL-5 and IL-13. These data further support the role of TSLP as initial trigger of allergic T cell responses and suggest that CD40L-expressing cells may act in combination with TSLP to amplify and sustain pro-allergic responses and cause tissue damage by promoting the generation of IFN-γ–producing cytotoxic effectors

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies

TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis

Regulatory T-cell development in the human thymus

© 2015 Caramalho, Nunes-Cabaço, Foxall and Sousa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The thymus generates a lineage-committed subset of regulatory T-cells (Tregs), best identified by the expression of the transcription factor FOXP3. The development of thymus-derived Tregs is known to require high-avidity interaction with MHC-self peptides leading to the generation of self-reactive Tregs fundamental for the maintenance of self-tolerance. Notwithstanding their crucial role in the control of immune responses, human thymic Treg differentiation remains poorly understood. In this mini-review, we will focus on the developmental stages at which Treg lineage commitment occurs, and their spatial localization in the human thymus, reviewing the molecular requirements, including T-cell receptor and cytokine signaling, as well as the cellular interactions involved. An overview of the impact of described thymic defects on the Treg compartment will be provided, illustrating the importance of these in vivo models to investigate human Treg development.IC, HN-C, and RBF received scholarships from Fundação para a Ciência e a Tecnologia (FCT) cofinanced by Programa Operacional Ciência e Inovação 2010 (POCI2010)

Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction

Plasmacytoid dendritic cells (pDCs) produce copious type I interferon (IFN) upon sensing nucleic acids through Toll-like receptor (TLR) 7 and TLR9. Uncontrolled pDC activation and IFN production are implicated in lymphopenia and autoimmune diseases; therefore, a mechanism controlling pDC IFN production is essential. Human pDCs specifically express an orphan receptor, immunoglobulin-like transcript 7 (ILT7). Here, we discovered an ILT7 ligand expressed by human cell lines and identified it as bone marrow stromal cell antigen 2 (BST2; CD317). BST2 directly binds to purified ILT7 protein, initiates signaling via the ILT7–FcϵRIγ complex, and strongly inhibits production of IFN and proinflammatory cytokines by pDCs. Readily induced by IFN and other proinflammatory cytokines, BST2 may modulate the human pDC’s IFN responses through ILT7 in a negative feedback fashion

Progress and challenges in the vaccine-based treatment of head and neck cancers

Head and neck (HN) cancer represents one of the most challenging diseases because the mortality remains high despite advances in early diagnosis and treatment. Although vaccine-based approaches for the treatment of advanced squamous cell carcinoma of the head and neck have achieved limited clinical success, advances in cancer immunology provide a strong foundation and powerful new tools to guide current attempts to develop effective cancer vaccines. This article reviews what has to be rather what has been done in the field for the development of future vaccines in HN tumours

The role of thymic tolerance in CNS autoimmune disease

The contributions of the peripheral adaptive and innate immune systems to CNS autoimmunity have been extensively studied. However, the role of thymic selection in these conditions is much less well understood. The thymus is the primary lymphoid organ for the generation of T cells; thymic mechanisms ensure that cells with an overt autoreactive specificity are eliminated before they emigrate to the periphery and control the generation of thymic regulatory T cells. Evidence from animal studies demonstrates that thymic T cell selection is important for establishing tolerance to autoantigens. However, there is a considerable knowledge gap regarding the role of thymic selection in autoimmune conditions of the human CNS. In this Review, we critically examine the current body of experimental evidence for the contribution of thymic tolerance to CNS autoimmune diseases. An understanding of why dysfunction of either thymic or peripheral tolerance mechanisms rarely leads to CNS inflammation is currently lacking. We examine the potential of de novo T cell formation and thymic selection as novel therapeutic avenues and highlight areas for future study that are likely to make these targets the focus of future treatments