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Objective: Neonatal hypoxic-ischemic encephalopathy (HIE) is caused by brain injury that occurs in a developing fetus or infant. Stem cell transplantation can reportedly induce functional recovery in animal models of HIE. Murine neonatal splenocytes are enriched with immature blood stem cells and are used for the investigation of murine models of syngeneic transplantation. The aim of this study was to investigate the therapeutic potential of newborn splenocytes in a murine model of neonatal ischemia-reperfusion brain injury. Methods: C57BL/6N mice (postnatal day 7) underwent right common carotid artery occlusion with an aneurysm clip. Following hypoxic exposure, reperfusion was achieved by unclamping the artery. Newborn splenocytes were transplanted intravenously at 3 weeks after injury. Results: The splenocytes transplanted group tended to show an improvement in behavioral tests, but it was not significantly different compared with the control groups. The transplanted cells were localized in various organs including injured brain tissue over 3 weeks. In the penumbra region of the brain, vascular endothelial growth factor (VEGF) expression was upregulated after transplantation. Conclusions: These results showed that syngeneic transplantation of newborn splenocytes achieved the long-term survival of the grafts and exerted influence the microenvironment in the injured brains of mice. [ABSTRACT FROM AUTHOR]

Abstract: The low molecular weight compound VAF347, and its pro-drug version VAG539, interact with the transcription factor aryl hydrocarbon receptor (AhR) on monocytes to mediate its anti-inflammatory activity in vitro and in vivo. AhR is a crucial factor for IL-22 production, which regulates skin and gut homeostasis. Here we investigated whether VAF347 might control the differentiation of naïve T cells into IL-22-secreting cells and/or regulate IL-22 production by memory T cells. Human monocytes exposed to VAF347 differentiated into dendritic cells capable of instructing a naïve CD4+ T cell differentiation program that promoted IL-22 secretion and concomitantly inhibited IL-17 production. Whilst AhR ligation by VAF347 on naïve CD4+ T cells favored the development of single IL-22-secreting cells (Th22), it suppressed the generation of T cells secreting either IL-22 and IFN-γ or IL-17 and IFN-γ. In contrast, memory T cells were refractory to AhR regulation since VAF347, AhR antagonist or AhR gene silencing did not modulate the production of any of these cytokines. Interfering with AhR functions using VAF347 may provide an efficient way to intervene with autoimmune disease since it would enhance the host protective function mediated by IL-22 while preventing the development of Th cells secreting pro-inflammatory cytokines. [Copyright &y& Elsevier]

How do effector CD4 T cells escape cell death during the contraction of the immune response (IR) remain largely unknown. CD47, through interactions with thrombospondin-1 (TSP-1) and SIRP-α, is implicated in cell death and phagocytosis of malignant cells. Here, we reported a reduction in SIRP-α- Fc binding to effector memory T cells (TEM) and in vitro TCR- activated human CD4 T cells that was linked to TSP-1/CD47-induced cell death. The reduced SIRP-α-Fc binding (CD47low status) was not detected when CD4 T cells were stained with two anti-CD47 mAbs, which recognize distinct epitopes. In contrast, increased SIRP-α-Fc binding (CD47high status) marked central memory T cells (TCM) as well as activated CD4 T cells exposed to IL-2, and correlated with resistance to TSP-1/CD47-mediated killing. Auto-aggressive CD4 effectors, which accumulated in lymph nodes and at mucosal sites of patients with Crohn's disease, displayed a CD47high status despite a high level of TSP-1 release in colonic tissues. In mice, CD47 (CD47low status) was required on antigen (Ag)-specific CD4+/+ effectors for the contraction of the IR in vivo, as significantly lower numbers of Ag-specific CD47+/+CD4 T cells were recovered when compared to Ag-specific CD47-/- CD4T cells. In conclusion, we demonstrate that a transient change in the status of CD47, i.e. from CD47high> to CD47low, on CD4 effectors regulates the decision-making process that leads to CD47-mediated cell death and contraction of the IR while maintenance of a CD47high status on tissue-destructive CD4 effectors prevents the resolution of the inflammatory response. [ABSTRACT FROM AUTHOR]

We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (Pcombined = 3.49 × 10−9, odds ratio = 1.78, confidence interval = 1.47–2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1β production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease. [ABSTRACT FROM AUTHOR]

T cell memory is the hallmark of adaptive immunity. Central questions are to determine which cells among proliferating effector T cells will live beyond the crash of the immune response (IR) and develop into functional memory T cells. CD47, considered as a marker of self, is implicated in cell death, cell elimination, and in the inflammatory response. We report in this article that CD47 expression was transiently regulated on Ag-specific CD4 T cells, that is, from CD47high to CD47low to CD47high, during the course of the in vivo IR. Specifically, CD47high status marked central memory CD4 T cell precursors at an early time point of the IR. By contrast, cytokine production was a functional attribute restricted to CD47high, but not CD47low, polyclonal effector CD4 T cells during recall responses in an experimental model of chronic airway inflammatory disease. Passive transfer of CD47high, but not CD47low, CD4 T cells in nonlymphopenic naive mice generated long-lived memory T cells capable of anamnestic responses. We conclude that CD47high status on CD4 T cells identifies functional long-lived memory T cell progenitors. [ABSTRACT FROM AUTHOR]

The balance between effector CD4(+) T cells secreting IL-17 (T(h)17) and regulatory T cells (Treg) plays an important role in autoimmune disorders that include rheumatoid arthritis (RA) and Crohn's disease. Tumor necrosis factor (TNF)-alpha is a key pro-inflammatory cytokine that contributes to disease pathogenesis. We investigated the interplay between CD45RA(+) Treg and TNF-alpha in the regulation of human T(h)17 differentiation. We found that CD45RA(+) Treg promoted while TNF-alpha inhibited naive CD4(+) T-cell differentiation into IL-17 and CCL20 co-expressing T(h)17 cells without influencing their IL-22 release. Unexpectedly, CD45RA(+) Treg depletion abrogated TNF-alpha suppressive function. Finally, dendritic cell-derived TNF-alpha suppressed the development of IL-17(+)CCL20(+) expressing T(h)17 cells. In conclusion, CD45RA(+) Treg positively governs human T(h)17 development, which is impaired by TNF-alpha. We propose that TNF-alpha may represent a negative feedback mechanism to control IL-17/CCL20- but not IL-22-associated autoimmune pathologies.

Thymus-derived CD4+ CD25+ T regulatory cells (Tregs) are essential for the maintenance of self-tolerance. What critical factors and conditions are required for the extra-thymic development of Tregs remains an important question. In this study, we show that the anti-inflammatory extracellular matrix protein, thrombospondin-1, promoted the generation of human peripheral regulatory T cells through the ligation of one of its receptor, CD47. CD47 stimulation by mAb or a thrombospondin-1 peptide induced naive or memory CD4+ CD25- T cells to become suppressive. The latter expressed increased amounts of CTLA-4, OX40, GITR, and Foxp3 and inhibited autologous Th0, Th1, and Th2 cells. Their regulatory activity was contact dependent, TGF-beta independent, and partially circumvented by IL-2. This previously unknown mechanism to induce human peripheral Tregs in response to inflammation may participate to the limitation of collateral damage induced by exacerbated responses to self or foreign Ags and thus be relevant for therapeutic intervention in autoimmune diseases and transplantation.