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James P. DiSanto

Bio: James P. DiSanto is an academic researcher from Necker-Enfants Malades Hospital. The author has contributed to research in topics: Cytotoxic T cell & T cell. The author has an hindex of 8, co-authored 11 publications receiving 1524 citations.

Papers
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Journal ArticleDOI
11 Feb 1993-Nature
TL;DR: CD40L transcripts in four unrelated male children with the hyper-IgM syndrome showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.
Abstract: Signalling for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T-B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein with homology to tumour necrosis factor-alpha and -beta, and has important functions in B-cell activation and differentiation. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.

693 citations

Journal ArticleDOI
01 Aug 1999-Immunity
TL;DR: In this paper, the in vivo differentiation of CD4 T cells from naive to memory cells was followed after their adoptive transfer together with syngeneic dendritic cells into MHC mismatched adoptive hosts lacking lymphocytes and NK cells.

220 citations

Journal ArticleDOI
TL;DR: It is proposed that, when activated by their cognate ligands and/or IL‐12 produced by cells in the lamina propria, IEL eliminate infected and senescent epithelial cells through a combination of cytotoxicity and of IFN‐γ and TNF release, which insures the rapid epithelial renewal of the villi, which helps maintain the functional integrity of the barrier.
Abstract: The small bowel mucosa contains within its villus epithelium a large number of intraepithelial lymphocytes (IEL) which upon activation are cytotoxic and release large quantities of IFN-gamma and TNF; these activities are increased by in vitro exposure to IL-12. Mice injected with IL-12 develop severe damage of the villus epithelial cells, in form of apoptosis, necrosis and a third distinct form of cell death, characterized ultrastructurally by progressive cell shrinkage. These lesions are accompanied by a compensatory acceleration of the epithelial renewal, a hallmark of epithelial injury. Use of a variety of mutant mice showed that these lesions require the presence of IEL (all populations being involved, thymus-dependent as well as natural killer-T cell IEL) and the release of IFN-gamma. The critical role of IFN-gamma may result in part from its capacity to induce on epithelial cells the expression of target molecules involved in the different cytotoxic pathways used by IEL. However, injection of IFN-gamma into mutant mice lacking IEL showed that IFN-gamma can directly induce villus epithelial damage as well. On the other hand, injection of TNF induces fulminant apoptosis of villus epithelial cells, starting at the top of the villi; however TNF is not required for IL-12-induced enteropathy, which is unmodified in mutant mice lacking TNF. We propose that, when activated by their cognate ligands and/or IL-12 produced by cells in the lamina propria, IEL eliminate infected and senescent epithelial cells through a combination of cytotoxicity and of IFN-gamma and TNF release. This insures the rapid epithelial renewal of the villi, which in turn helps maintain the functional integrity of the barrier.

207 citations

Journal ArticleDOI
TL;DR: The TCR-αβ can assume a role not only in the rescue from programmed cell death of CD4+8+ but also ofCD4−8− thymocytes, and may have been responsible for the maturation of αβ T cells before the advent of the pre–TCR-α chain.
Abstract: The development of pre–T cells with productive TCR-β rearrangements can be mediated by each the pre–T cell receptor (pre-TCR), the TCR-αβ as well as the TCR-γδ, albeit by distinct mechanisms. Although the TCR-γδ affects CD4−8− precursor cells irrespective of their rearrangement status by TCR-β mechanisms not involving TCR-β selection, both the preTCR and the TCR-αβ select only cells with productive TCR-β genes for expansion and maturation. The TCR-αβ appears to be much less effective than the pre-TCR because of the paucity of TCR-α proteins in TCR-β–positive precursors since an early expressed transgenic TCR-αβ can largely substitute for the pre-TCR. Thus, the TCR-αβ can assume a role not only in the rescue from programmed cell death of CD4+8+ but also of CD4−8− thymocytes. In evolution this double function of the TCR-αβ may have been responsible for the maturation of αβ T cells before the advent of the pre–TCR-α chain.

108 citations

Journal ArticleDOI
TL;DR: The findings support the assignment of pregnancy-associated large granulated cells of mice to the NK cell lineage and suggest that the primary functions of these tissue-based NK cells are to support normal development of the decidua and/or its vasculature using pathways that involve IL-12 mediated signal transduction.

89 citations


Cited by
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Journal ArticleDOI
01 Sep 2000-Cell
TL;DR: Results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation in CH12F3-2 B lymphoma.

3,288 citations

Journal ArticleDOI
28 Jan 1994-Cell

1,890 citations

Journal ArticleDOI
TL;DR: Critical roles for IL-15 in the development of specific lymphoid lineages are revealed and the ability to rescue lymphoid defects inIL-15−/− mice by IL- 15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.
Abstract: C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

1,586 citations

Journal ArticleDOI
01 Sep 2000-Cell
TL;DR: The phenotype observed in HIGM2 patients (and in AID-/- mice) demonstrates the absolute requirement for AID in several crucial steps of B cell terminal differentiation necessary for efficient antibody responses.

1,551 citations

Journal ArticleDOI
TL;DR: It is demonstrated that dendritic Langerhans cells (D-Lc) generated by culturing cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating and tumor necrosis factor alpha (TNF-alpha) express functional CD40 at a density higher than that found on B cells.
Abstract: Dendritic cells, the professional antigen-presenting cells (APC) involved in T cell priming, express CD40, a molecule which triggering plays a key role in B cell growth and differentiation as well as monocyte activation. Herein we demonstrate that dendritic Langerhans cells (D-Lc) generated by culturing cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating and tumor necrosis factor alpha (TNF-alpha) express functional CD40 at a density higher than that found on B cells. Culturing D-Lc on CD40-ligand (CD40L) transfected L cells allowed D-Lc survival as 50 +/- 15% of seeded cells were recovered after 4 d while only 5% survived over control L cells. CD40 activation induced important morphological changes with a reduction of cytoplasmic content and a remarkable increase of dendrite development as well as an altered phenotype. In particular, CD40 triggering induced maintenance of high levels of major histocompatibility complex class II antigens and upregulation of accessory molecules such as CD58, CD80 (B7-1) and CD86 (B7-2). CD40 engagement also seems to turn on D-Lc maturation as illustrated by upregulation of CD25, a molecule usually expressed on interdigitating dendritic cells of secondary lymphoid organs. Finally, CD40 activated D-Lc secreted a limited set of cytokines (TNF-alpha, IL-8, and macrophage inflammatory protein 1 alpha [MIP-1 alpha]) whereas a similar activation induced elutriated monocytes to secrete IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, TNF-alpha, and MIP-1 alpha. As D-Lc activated T cells upregulated CD40L, it is likely that CD40 activation of D-Lc observed herein with a fibroblast cell line stably expressing CD40L, mimics physiological interactions between dendritic cells and T cells.

1,429 citations