Marie-Claude Trescol-Biémont

Retraction: Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus

Nicole Boucheron, Roland Tschismarov, Lisa Goeschl, Mirjam A Moser, Sabine Lagger, Shinya Sakaguchi, Mircea Winter, Florian Lenz, Dijana Vitko, Florian P Breitwieser, Lena Müller, Hammad Hassan, Keiryn L Bennett, Jacques Colinge, Wolfgang Schreiner, Takeshi Egawa, Ichiro Taniuchi, Patrick Matthias, Christian Seiser& Wilfried Ellmeier Nat. Immunol. 15, 439–448 (2014); published online 30 March 2014; corrected after print 6 June 2014

Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival

Intraperitoneal peptide injection of TCR‐transgenic mide or expression of antigen in hepatocytes leads to an accumulation in the liver of specific apoptotic CD8+ T cells expressing activation markers. To determine whether liver cells are capable of directly activating naive CD8+ T cells, we have studied the ability of purified hepatocytes to activate TCR‐transgenic CD8+ T cells in vitro. We show that hepatocytes which do not express CD80 and CD86 co‐stimulatory molecules are able to induce activation and effective proliferation of specific naive CD8+ T cells in the absence of exogenously added cytokines, a property only shared by professional antigen‐presenting cells (APC). Specific T cell proliferation induced by hepatocytes was comparable in magnitude to that seen in response to dendritic cells and was independent of CD4+ T cell help or bystander professional APC co‐stimulation. During the first 3 days, the same number of divisions was observed in co‐cultures of CD8+ T cells with either hepatocytes or splenocytes. Both APC populations induced expression of early T cell activation markers and specific cytotoxic T lymphocyte (CTL) activity. However, in contrast to T cells activated by splenocytes, T cells activated by hepatocytes lost their cytolytic function after 3 days of co‐culture. This correlated with death of activated T cells, suggesting that despite efficient activation, proliferation and transient CTL function, T cells activated by hepatocytes did not survive. Death could be prevented by adding antigen‐expressing splenocytes or exogenous IL‐2 to the co‐culture, indicating that hepatocytes are not involved in direct killing of CD8+ T cells but rather fail to promote survival. Dying cells acquired a CD8low TCRlow B220+ phenotype similar to the one described for apoptotic intrahepatic T cells, suggesting an alternative model to account for the origin of these cells in the liver. The importance of these findings for the understanding of peripheral tolerance and the ability of liver grafts to be accepted is discussed.

Mechanism of Measles Virus–Induced Suppression of Inflammatory Immune Responses

Measles virus (MV) causes profound immunosuppression, resulting in high infant mortality. The mechanisms are poorly understood, largely due to the lack of a suitable animal model. Here, we report that particular MV proteins, in the absence of MV replication, could generate a systemic immunosuppression in mice through two pathways: (1) via MV-nucleoprotein and its receptor FcgammaR on dendritic cells; and (2) via virus envelope glycoproteins and the MV-hemagglutinin cellular receptor, CD46. The effects comprise reduced hypersensitivity responses associated with impaired function of dendritic cells, decreased production of IL-12, and the loss of antigen-specific T cell proliferation. These results introduce a novel model for testing the immunosuppressive potential of anti-measles vaccines and reveal a specific mechanism of MV-induced modulation of inflammatory reactions.

Cutting Edge: CD46, a New Costimulatory Molecule for T Cells, That Induces p120CBL and LAT Phosphorylation

The widely expressed transmembrane molecule CD46 is the complement regulatory receptor for C3b as well as the receptor for several pathogens. Beside its binding functions, CD46 is also able to transduce signals. We showed that CD46 aggregation on human T cells induces p120CBL and linker for activation of T cells (LAT) phosphorylation. These two proteins are adaptor proteins known to regulate TCR signaling. p120CBL is a complex adaptor protein involved in negatively regulating signaling events, whereas LAT is a transmembrane adaptor protein found in glycolipid-enriched microdomains essential for T cell activation. Therefore, we investigated if a CD46/TCR costimulation would affect T cell activation. Indeed, CD46/CD3 costimulation strongly promotes T cell proliferation. Therefore, we propose that CD46 acts as a potent costimulatory molecule for human T cells.

Measles Virus (MV) Nucleoprotein Binds to a Novel Cell Surface Receptor Distinct from FcγRII via Its C-Terminal Domain: Role in MV-Induced Immunosuppression

ABSTRACT During acute measles virus (MV) infection, an efficient immune response occurs, followed by a transient but profound immunosuppression. MV nucleoprotein (MV-N) has been reported to induce both cellular and humoral immune responses and paradoxically to account for immunosuppression. Thus far, this latter activity has been attributed to MV-N binding to human and murine FcγRII. Here, we show that apoptosis of MV-infected human thymic epithelial cells (TEC) allows the release of MV-N in the extracellular compartment. This extracellular N is then able to bind either to MV-infected or uninfected TEC. We show that recombinant MV-N specifically binds to a membrane protein receptor, different from FcγRII, highly expressed on the cell surface of TEC. This new receptor is referred to as nucleoprotein receptor (NR). In addition, different Ns from other MV-related morbilliviruses can also bind to FcγRII and/or NR. We show that the region of MV-N responsible for binding to NR maps to the C-terminal fragment (NTAIL). Binding of MV-N to NR on TEC triggers sustained calcium influx and inhibits spontaneous cell proliferation by arresting cells in the G0 and G1 phases of the cell cycle. Finally, MV-N binds to both constitutively expressed NR on a large spectrum of cells from different species and to human activated T cells, leading to suppression of their proliferation. These results provide evidence that MV-N, after release in the extracellular compartment, binds to NR and thereby plays a role in MV-induced immunosuppression.

Productive Measles Virus Brain Infection and Apoptosis in CD46 Transgenic Mice

ABSTRACT Measles virus (MV) infection causes acute childhood disease, associated in certain cases with infection of the central nervous system (CNS) and development of neurological disease. To develop a murine model of MV-induced pathology, we generated several lines of transgenic mice ubiquitously expressing as the MV receptor a human CD46 molecule with either a Cyt1 or Cyt2 cytoplasmic tail. All transgenic lines expressed CD46 protein in the brain. Newborn transgenic mice, in contrast to nontransgenic controls, were highly sensitive to intracerebral infection by the MV Edmonston strain. Signs of clinical illness (lack of mobility, tremors, and weight loss) appeared within 5 to 7 days after infection, followed by seizures, paralysis, and death of the infected animals. Virus replication was detected in neurons from infected mice, and virus was reproducibly isolated from transgenic brain tissue. MV-induced apoptosis observed in different brain regions preceded the death of infected animals. Similar results were obtained with mice expressing either a Cyt1 or Cyt2 cytoplasmic tail, demonstrating the ability of different isoforms of CD46 to function as MV receptors in vivo. In addition, maternally transferred immunity delayed death of offspring given a lethal dose of MV. These results document a novel CD46 transgenic murine model where MV neuronal infection is associated with the production of infectious virus, similarly to progressive infectious measles encephalitis seen in immunocompromised patients, and provide a new means to study pathogenesis of MV infection in the CNS.

ENHANCED MHC CLASS II-RESTRICTED PRESENTATION OF MEASLES VIRUS (MV) HEMAGGLUTININ IN TRANSGENIC MICE EXPRESSING HUMAN MV RECEPTOR CD46

This study analyzes the role of the measles virus (MV) receptor, i.e. the human CD46 molecule, in the MHC class II‐restricted presentation of MV hemagglutinin (H). We generated transgenic mice ubiquitously expressing CD46, with a similar level of transgene expression on the surface of antigen‐presenting cells (APC), i.e. B cells, dendritic cells (DC) and macrophages. APC isolated from transgenic mice and nontransgenic controls were tested for their ability to present MV H to H‐specific CD4+ I‐E d ‐restricted T cell hybridomas. All three populations of APC were capable of presenting MV to T cell hybridomas, DC being the most efficient. Expression of CD46 on B lymphocytes increased MHC class II‐dependent presentation of MV H up to 100‐fold, while CD46‐transgenic DC stimulated H‐specific T cell hybridomas up to 10‐fold better than nontransgenic DC. Interestingly, expression of CD46 did not change the presentation efficiency of transgenic macrophages, indicating that CD46‐dependent enhancement of antigen presentation depends on the nature of the APC. Furthermore, a single injection of UV‐inactivated MV particles into CD46‐transgenic mice, but not nontransgenic controls, induced generation of MV‐specific T lymphocytes and production of anti‐H antibodies, suggesting a role for CD46 in the efficient capture of MV in vivo. These results show for the first time that one ubiquitously expressed cell surface receptor, like CD46, could function in receptor‐mediated antigen presentation both in vitro and in vivo and its performance depends on the type of APC which expresses it.

Can one predict antigenic peptides for MHC class I-restricted cytotoxic T lymphocytes useful for vaccination?

The cytotoxic T-lymphocyte (CTL) response can be crucial for efficient immunological control of intracellular pathogens and the MHC class I-restricted CTL have a major role to play in this process. They recognize complexes associating antigen-derived peptides with MHC class I molecules expressed on infected target cells. The characterization of these antigenic peptides is thus a key issue for developing vaccines efficient in inducing specific CTL. Recently, by sequencing the whole set of self-peptides eluted from a given MHC class I molecule, Falk and colleagues have found that they have a homogeneous 8-10 residue length and contain allele-specific peptidic motifs with two conservative dominant anchor residues. The existence of consensus motifs opens the way for a strategy to predict the MHC class I-restricted T-cell epitopes and here we discuss such an approach using hen egg lysozyme (HEL) as an antigenic model. Two HEL peptides corresponding to allele-specific motifs were found, HEL(49-56) and HEL(70-78) peptides, which can associate with MHC class I H-2Kb and H-2Db molecules, respectively. The HEL peptide HEL(70-78) was found to be able to induce HEL-specific CTL in H-2b mice also. Moreover, using an empiricial approach, we have also characterized the N-terminal HEL(1-17) peptide as an immunodominant antigenic peptide in the H-2k haplotype. This peptide presented by H-2Kk molecules neither contained the corresponding allele-specific binding motif nor fitted the expected 8-10 residue length.(ABSTRACT TRUNCATED AT 250 WORDS)

C-terminal Residues Regulate Localization and Function of the Antiapoptotic Protein Bfl-1

Unlike other antiapoptotic members of the Bcl-2 family, Bfl-1 does not contain a well defined C-terminal transmembrane domain, and whether the C-terminal tail of Bfl-1 functions as a membrane anchor is not yet clearly established. The molecular modeling study of the full-length Bfl-1 performed within this work suggests that Bfl-1 may co-exist in two distinct conformational states: one in which its C-terminal helix α9 is inserted in the hydrophobic groove formed by the BH1–3 domains of Bfl-1 and one with its C terminus. Parallel analysis of the subcellular localization of Bfl-1 indicates that even if Bfl-1 may co-exist in two distinct conformational states, most of the endogenous protein is tightly associated with the mitochondria by its C terminus in both healthy and apoptotic peripheral blood lymphocytes as well as in malignant B cell lines. However, the helix α9 of Bfl-1, and therefore the binding of Bfl-1 to mitochondria, is not absolutely required for the antiapoptotic activity of Bfl-1. A particular feature of Bfl-1 is the amphipathic character of its C-terminal helix α9. Our data clearly indicate that this property of helix α9 is required for the anchorage of Bfl-1 to the mitochondria but also regulates the antiapoptotic function Bfl-1.

An accessory peptide binding site with allosteric effect on the formation of peptide-MHC-II complexes?

MHC-II molecules bind a single peptide in their groove. Here, the authors summarise evidence that a second peptide could bind transiently to MHC-II molecules outside the groove and have an allosteric effect on peptide-MHC-II complex formation. This effect could modulate, after the antigen processing, the selection of the peptide subset presented by MHC-II molecules to the helper CD4 T cells, which regulate the specific immune response.