Françoise Le Deist

Measles Virus Induces Abnormal Differentiation of CD40 Ligand-Activated Human Dendritic Cells

Measles virus (MV) infection induces a profound immunosuppression responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DCs) in the respiratory mucosa or in the secondary lymphoid organs. The purpose of this study was to investigate the consequences of DC infection by MV, particularly concerning their maturation and their ability to generate CD8+ T cell proliferation. We first show that MV-infected Langerhans cells or monocyte-derived DCs undergo a maturation process similarly to the one induced by TNF-α or LPS, respectively. CD40 ligand (CD40L) expressed on activated T cells is shown to induce terminal differentiation of DCs into mature effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression down-regulation. Moreover, the CD40L-induced cytokine pattern in DCs is modified by MV infection with inhibition of IL-12 and IL-1α/β and induction of IL-10 mRNAs synthesis. Using peripheral blood lymphocytes from CD40L-deficient patients, we demonstrate that MV infection of DCs prevents the CD40L-dependent CD8+ T cell proliferation. In such DC-PBL cocultures, inhibition of CD80 and CD86 expression on DCs was shown to require both MV replication and CD40 triggering. Finally, for the first time, MV was shown to inhibit tyrosine-phosphorylation level induced by CD40 activation in DCs. Our data demonstrate that MV replication modifies CD40 signaling in DCs, thus leading to impaired maturation. This phenomenon could play a pivotal role in MV-induced immunosuppression.

Cell-death signaling and human disease

The autoimmune lymphoproliferative syndrome (ALPS) in humans and the lpr mouse strain are the first examples of primary apoptosis defects caused by inherited death-receptor mutations. They illustrate the role of Fas and Fas ligand in the control of autoimmune T-cell and B-cell proliferation. Subsequent analyses of ALPS in humans have highlighted the role of caspase 10 in the induction of apoptosis. The recent identification of a human caspase 8 defect has revealed a potential connection between apoptosis pathways and immune-receptor signaling. The genetic basis of ALPS is extremely complex, as multiple factors are potentially involved in the pathogenesis of this disease, thus offering an interesting model with which to unravel the mechanisms involved in T-cell homeostasis and self-tolerance.

T Cell-Dependent Activation of Dendritic Cells Requires IL-12 and IFN-γ Signaling in T Cells

Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4+ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN-γ producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4+ T cells to induce IL-12 secretion by DCs. These data suggest that CD4+ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.

Artemis sheds new light on V(D)J recombination.

Summary:u2002 V(D)J recombination represents one of the three mechanisms that contribute to the diversity of the immune repertoire of B lymphocytes and T lymphocytes. It also constitutes a major checkpoint during the development of the immune system. Indeed, any V(D)J recombination deficiency leads to a block of B‐cell and T‐cell maturation in humans and animal models, leading to severe combined immunodeficiency (T‐B‐SCID). Nine factors have been identified so far to participate in V(D)J recombination. The discovery of Artemis, mutated in a subset of T‐B‐SCID, provided some new information regarding one of the missing V(D)J recombinase activities: hairpin opening at coding ends prior to DNA repair of the recombination activating genes 1/2‐generated DNA double‐strand break. New conditions of immune deficiency in humans are now under investigations and should lead to the identification of additional V(D)J recombination/DNA repair factors.

A familial occurrence of natural killer cell‐T‐lymphocyte proliferation disease in two children

Several reports describe the association of hyperlymphocytosis with neutropenia. This syndrome, named lymphoproliferative disease, is characterized by a chronic indolent clinical course, bone marrow lymphocyte infiltration, and granulopenia of central origin. The proliferating lymphocytes share large granular lymphocyte natural killer cell and T‐lymphocyte characteristics. They are either of monoclonal or polyclonal origin. In this report the familial occurrence of a similar syndrome observed in two children is described. Lymphocyte morphologic abnormalities including nuclear pockets, were noted, a feature usually present in leukemic cells. Lymphocyte proliferation was distinct in each case as shown by the presence of a predominant CD4+ cell population in one and a predominant CD8+ population in the other. Monoclonal gene rearrangements of T‐cell receptor β‐chain gene were found although clonal variations occurred with time in one patient. The cause of this unique familial occurrence of monoclonal lymphoproliferation associated with neutropenia is unknown.

HML-1, A Novel Integrin Made of the β7 Chain and of a Distinctive α Chain, Exerts an Accessory Function in the Activation of Human IEL via the CD3-TCR Pathway

Intestinal intraepithelial lymphocytes (EEL) form a large population of T cells located at the interface between the body and the intestinal lumen. They differ from T cells in other lymphoid compartments by their phenotype, mainly CD3+CD8+, the elevated proportion of TcR gd+ cells, their dual thymo-dependent and -independent origin, their cytotoxic properties and their microenvironment in the immediate vicinity of epithelial cells, at some distance from the usual partners of the immune response.1,2 The hypothesis that IEL possess specific surface receptors enabling interactions with local ligands and controlling their homing, differentiation and/or activation, led us to seek membrane antigens expressed on IEL but not on lymphocytes in other lymphoid organs. One monoclonal antibody, HML-1, raised against human IEL defined a novel membrane antigen preferentially expressed by IEL in the human intestine and in other epithelia (that we will hereafter refer to as MLA for mucosal lymphocyte antigen). Interestingly, in humans, the antibody HML-1 was found to label rare intestinal T cell lymphomas associated with an enteropathy and hyperplasia of IEL, sustaining a previous hypothesis of the intraepithelial origin of such lymphomas4 and HML-1 labelling was also observed on abnormal cells in mycosis fungoides with marked epidermotropism.5 However, the expression of this membrane antigen was not entirely restricted to normal or tumoral IEL as it appeared on activated T cells, mainly CD8+6,7 Furthermore, HML-1 labelling appeared to be an almost constant phenotypical feature of hairy B cell leukemia.7-9 In spite of this not entirely specific expression, the antigen defined by HML-1 seemed to be an interesting antigen and a potential candidate for mediating interactions between IEL and enterocytes.