Human Cytomegalovirus Entry into Dendritic Cells Occurs via a Macropinocytosis-Like Pathway in a pH-Independent and Cholesterol-Dependent Manner

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to infect fibroblastic, epithelial, endothelial and hematopoietic cells. Over the past ten years, several groups have provided direct evidence that dendritic cells (DCs) fully support the HCMV lytic cycle. We previously demonstrated that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) has a prominent role in the docking of HCMV on monocyte-derived DCs (MDDCs). The DC-SIGN/HCMV interaction was demonstrated to be a crucial and early event that substantially enhanced infection in trans, i.e., from one CMV-bearing cell to another non-infected cell (or trans-infection), and rendered susceptible cells fully permissive to HCMV infection. Nevertheless, nothing is yet known about how HCMV enters MDDCs. In this study, we demonstrated that VHL/E HCMV virions (an endothelio/dendrotropic strain) are first internalized into MDDCs by a macropinocytosis-like process in an actin- and cholesterol-dependent, but pH-independent, manner. We observed the accumulation of virions in large uncoated vesicles with endosomal features, and the virions remained as intact particles that retained infectious potential for several hours. This trans-infection property was specific to MDDCs because monocyte-derived macrophages or monocytes from the same donor were unable to allow the accumulation of and the subsequent transmission of the virus. Together, these data allowed us to delineate the early mechanisms of the internalization and entry of an endothelio/dendrotropic HCMV strain into human MDDCs and to propose that DCs can serve as a "Trojan horse" to convey CMV from entry sites to other locations that may favor the occurrence of either latency or acute infection

Contribution à l'étude de l'immunosuppression et de l'induction de tolérance à l'allogreffe induite par des anticorps anti-CD28

L'activation du lymphocyte T nécessite deux signaux : un signal de reconnaissance antigénique et un signal de costimulation. Le CD28 peut transmettre ce signal de costimulation en liant les molécules B7-1 et -2 exprimées par les cellules présentatrices d'antigène. Ces récepteurs B7 possèdent un autre ligand, le CTLA-4, qui inhibe l'activation des cellules T et est responsable de la mise en place de mécanismes régulateurs. Ainsi, nous avons étudié l'hypothèse selon laquelle un blocage spécifique de la liaison CD28/B7, sans empêcher l'interaction CTLA-4/B7, serait immunosuppresseur et inducteur de tolérance. Dans un premier temps, nous avons montré que le blocage sélectif de CD28 inhibe les réponses T allogéniques " directes " mais pas les réponses à un antigène soluble. Ensuite, nous avons démontré qu'effectivement, ce blocage induit une tolérance à l'allogreffe rénale chez le rat qui s'accompagne du développement de cellules régulatrices non-T de phénotype CMH II- B7+.B7 interaction with CD28 is essential for optimal activation of naive T cells. On the other hand, B7 can interact with CTLA-4 which inhibits T cell activation and proliferation and facilitates the induction of regulatory mechanisms. Therefore, selectively inhibiting the B7/CD28 pathway, without blocking that of B7/CTLA-4, may be strongly immunosuppressive and may facilitate tolerance induction. We first demonstrated that the selective blockade of B7/CD28 interaction inhibits the T cell responses of the direct but not of the indirect pathway. Then, we showed, as initially suggested, that the selective inhibition of CD28 indeed induced kidney allograft tolerance in the rat. Regulatory mechanisms are found in the blood and the spleen of tolerant animals. They presented a non-T, CMH class II- B7+ phenotype.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Infectious Diseases in Transplantation—Report of the 20th Nantes Actualités Transplantation Meeting

International audienceThe 20th Nantes Actualités Transplantation (NAT) meeting was held on June 11, 2015, and June 12, 2015. This year, the local organizing committee selected an update on infectious diseases in solid organ and hematopoietic stem cell transplanta-tion. With an attendance of close to 170 clinicians, researchers, students, engineers, technicians, invited speakers, and guests from North and South America, Germany, Switzerland, Netherlands, and France, the meeting was well attended. Invited speakers' expertise covered basic as well as translational microbiology, immunology, transplantation, and intensive care medicine. This report identifies a number of advances presented during the meeting in the care and management of infectious diseases in transplanta-tion and immunocompromised patients. New antiviral immune responses and their modulation by pathogens in addition to novel antimicrobial therapeutic strategies, cell therapies, and genomic analysis were discussed

B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-αGAL–producing B-1 cells

B-1b cells produce IgM natural antibodies against α1-3Galβ1-4GlcNAc (αGal). These can be tolerized by nonmyeloablative induction of mixed chimerism using αGal-positive (αGal+) donor marrow. We assessed the role of CR1/2 in this model for induction of tolerance of B-1b cells. Mixed hematopoietic chimerism was induced in α1-3galactosyltransferase (GalT(−/−)) and GalT(−/−)Cr2(−/−) mice with αGal+ BALB/c marrow donors. Anti-αGal Ab and anti-αGal Ab–producing B cells became undetectable in GalT(−/−) chimeras, whereas they persisted in chimeric GalT(−/−)Cr2(−/−) mice. To determine whether CR1/2 expression on stromal cells and/or hematopoietic cells was critical for B-1–cell tolerance, we generated GalT(−/−) radiation chimeras in which CR1/CR2 was expressed on either stromal cells, hematopoietic cells, neither, or both. After induction of mixed chimerism from αGal+ allogeneic bone marrow (BM) donors, anti-αGal–producing B cells were rendered tolerant in reconstituted recipients expressing only stromal CR1/CR2. Our results suggest a possible role for follicular dendritic cells that pick up immune complexes via CR1/CR2 receptors in the tolerization of B-1b cells

The SIRP gene family : widespread conservation in animals, haplotypic polymorphisms in humans and its therapeutic consequences for monoclonal antibody reactivity

International audienc

Toward a better definition of hematopoietic progenitors suitable for B cell differentiation.

The success of inducing human pluripotent stem cells (hIPSC) offers new opportunities for cell-based therapy. Since B cells exert roles as effector and as regulator of immune responses in different clinical settings, we were interested in generating B cells from hIPSC. We differentiated human embryonic stem cells (hESC) and hIPSC into B cells onto OP9 and MS-5 stromal cells successively. We overcame issues in generating CD34+CD43+ hematopoietic progenitors with appropriate cytokine conditions and emphasized the difficulties to generate proper hematopoietic progenitors. We highlight CD31intCD45int phenotype as a possible marker of hematopoietic progenitors suitable for B cell differentiation. Defining precisely proper lymphoid progenitors will improve the study of their lineage commitment and the signals needed during the in vitro process