Teaching of English in French-Canada

Thesis (Ed.M.)--Boston University, 1935. This item was digitized by the Internet Archive

The epigenetic landscape of T cell exhaustion.

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection.

Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection

Endothelial Cell Activation and Proliferation Modulate NKG2D Activity by Regulating MICA Expression and Shedding

International audienceMICA are major histocompatibility complex class I-related molecules, expressed by endothelial cells (ECs), that may be targets for alloantibodies and NKG2D-expressing natural killer (NK) and T effector cells in organ allografts. This study shows that basal levels of MICA expressed on vascular ECs is sufficient to functionally modulate the expression and activity of the immunoreceptor NKG2D in allogeneic NK cells. We found that MICA expression is differentially regulated at the EC surface in response to cytokines. TNFα upregulates MICA while IFNγ significantly decreases MICA at the EC surface. Both cytokines induce the release of soluble MICA by ECs. Modulation of NKG2D correlates with the MICA level on the EC surface. Glycosylation and metalloproteinase activities account for major post-transcriptional mechanisms controlling MICA level and the function in ECs. Our results indicate that, in addition to the NFκB pathway, the mitogen-activated protein kinase pathways JNK, ERK1/2 and p38 are key signaling pathways in the control of MICA by the cytokines. Finally, we show that EC proliferation mediated by FGF-2 or wound healing increases the MICA level. Together, our data suggest that inflammation and proliferation regulate endothelial MICA expression and shedding, enabling ECs to modulate NKG2D activity on effector NK and T cells, and provide further evidence of a role for ECs in immunoregulation

Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions

International audienceMHC class I chain–related proteins A and B (MICA and MICB) and UL16-binding proteins are ligands of the activating NKG2D receptor involved in cancer and immune surveillance of infection. Structurally, MICA/B proteins contain an α3 domain, whereas UL16-binding proteins do not. We identified novel alternative splice transcripts for MICA encoding five novel MICA isoforms: MICA-A, -B1, -B2, -C, and -D. Alternative splicing associates with MICA*015 and *017 and results from a point deletion (G) in the 59 splice donor site of MICA intron 4 leading to exon 3 and exon 4 skipping and/or deletions. These changes delete the a3 domain in all isoforms, and the α2 domain in the majority of isoforms (A, B1, C, and D). Endothelial and hematopoietic cells contained endogenous alternative splice transcripts and isoforms. MICA-B1, -B2, and -D bound NKG2D by surface plasmon resonance and were expressed at the cell surface. Functionally, MICA-B2 contains two extracellular domains (α1 and α2) and is a novel potent agonist ligand for NKG2D. We found that MICA-D is a new truncated form of MICA with weak affinity for NKG2D despite lacking α2 and α3 domains. MICA-D may functionally impair NKG2D activation by competing with full-length MICA or MICA-B2 for NKG2D engagement. Our study established NKG2D binding for recombinant MICA-B1 but found no function for this isoform. New truncated MICA isoforms exhibit a range of functions that may drive unexpected immune mechanisms and provide new tools for immunotherapy

Discussion sur la partie du plan de l'abbé Sieyes relatif à l'organisation judiciaire concernant le jury, lors de la séance du 8 avril 1790

Malouet Pierre Victor, Garat (Aîné) Dominique, Clermont-Tonnerre Stanislas Marie, comte de. Discussion sur la partie du plan de l'abbé Sieyes relatif à l'organisation judiciaire concernant le jury, lors de la séance du 8 avril 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XII - Du 2 mars au 14 avril 1790. Paris : Librairie Administrative P. Dupont, 1881. pp. 587-592

Discussion sur l'affaire de l'investissement de la maison de M. de Clermont-Tonnerre, lors de la séance du 28 janvier 1791

Clermont-Tonnerre Stanislas Marie, comte de, Brocheton Charles Fabio, Babey Pierre-Marie-Athanase. Discussion sur l'affaire de l'investissement de la maison de M. de Clermont-Tonnerre, lors de la séance du 28 janvier 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXII - Du 3 janvier au 5 février 1791. Paris : Librairie Administrative P. Dupont, 1885. p. 523

Suite de la discussion sur l’affaire d’Avignon et du Comtat Venaissin, lors de la séance du 14 septembre 1791

Pétion de Villeneuve Jérome, Clermont-Tonnerre Stanislas Marie, comte de, Malouet Pierre Victor. Suite de la discussion sur l’affaire d’Avignon et du Comtat Venaissin, lors de la séance du 14 septembre 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXX - Du 28 août au 17 septembre 1791. Paris : Librairie Administrative P. Dupont, 1888. pp. 630-631

Discussion sur l'affaire de l'investissement de la maison de M. de Clermont-Tonnerre, lors de la séance du 28 janvier 1791

Clermont-Tonnerre Stanislas Marie, comte de, Brocheton Charles Fabio, Babey Pierre Marie Athanase. Discussion sur l'affaire de l'investissement de la maison de M. de Clermont-Tonnerre, lors de la séance du 28 janvier 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXII - Du 3 janvier au 5 février 1791. Paris : Librairie Administrative P. Dupont, 1885. p. 523