Analyse des altérations de l'immunité T-dépendante à l'égard de Candida albicans chez la souris transgénique exprimant le génome du VIH-1

La candidose oro-pharyngée (COP) est l’infection fongique opportuniste la plus commune chez les individus infectés par le VIH-1. La production des cytokines Il-17 et Il-22 par les lymphocytes Th17 est importante lors de la résolution de la COP, puisque ces cytokines induisent la production de peptides antifongiques et le recrutement des neutrophiles polymorphonucléaires. Toutefois, les lymphocytes Th17 sont préférentiellement déplétés chez les individus infectés par le VIH-1. Le modèle de COP chez la souris transgénique (Tg) CD4C/HIVMutA, exprimant les gènes nef, env et rev du VIH-1, permettra de déterminer si des altérations quantitatives et/ou fonctionnelles des sous-populations de lymphocytes T CD4+ causent la sensibilité à la candidose. Les sous-populations Th1, Th2, Th1Th17, Th17 et Treg, ainsi que leurs précurseurs, les lymphocytes T CD4+ naïfs, sont sévèrement déplétées dans les ganglions cervicaux de la souris Tg. Cependant, les lymphocytes T CD4+ naïfs conservent la capacité à se différencier in vitro en présence de cytokines polarisantes et à produire les cytokines typiques des diverses sous-populations. De plus, les cytokines requises pour la polarisation des lymphocytes T CD4+ naïfs n’étaient pas réduites dans les ganglions cervicaux des souris Tg, 7 jours après le début de l’infection. Les gènes S100a8, Ccl20, Il17 et Il22 étaient surexprimés en réponse à la COP chez la souris non-Tg, mais pas chez la souris Tg. Le traitement de souris Tg infectées à l’aide de la combinaison des cytokines Il-17 et Il-22 réduit significativement la charge fongique buccale de C. albicans et le nombre d’hyphes dans l’épithélium de la langue et restaure la capacité à surexprimer des gènes S100a8, Ccl20 et Il22. Ces résultats démontrent que la perturbation de l’induction de l’immunité innée par l’Il-17 et l’Il-22 augmente la susceptibilité à la COP chez la souris Tg.Oropharyngeal candidiasis (OPC) is the most common opportunistic fungal infection in HIV-infected individuals. OPC resolution involves Il-17 and Il-22 production by Th17 cells through oral antifungal peptide production and polymorphonuclear neutrophil recruitment. Conversely, Th17 cells are preferentially depleted in HIV-infected individuals. The OPC model in transgenic (Tg) mice expressing nef, env and rev from the HIV-1 genome enables the study of the quantitative and functional defects of the CD4+ T-cell subpopulations. The Th1, Th2, Th1Th17, Th17 and Treg subpopulations, as well as naïve CD4+ T-cell precursors, are severely depleted in the cervical lymph nodes (CLNs) of Tg mice. However, the differentiation capacity of naïve CD4+ T-cells in response to polarizing cytokines was maintained in vitro in Tg mice, as well as their ability to produce the signature cytokines of the various subpopulations. Moreover, the polarizing cytokines were not reduced in the CLNs of Tg mice, 7 days after infection. The S100a8, Ccl20, Il17 and Il22 genes were up-regulated in response to OPC in non-Tg mice, but not in Tg mice. Treatment of infected Tg mice with a combination of Il-17 and Il-22 cytokines significantly reduced the oral fungal burdens of C. albicans as well as the number of hyphae in the tongue epithelium. Treatment also restored S100a8, Ccl20 and Il22 up-regulation in Tg mice. These results show that defective induction of innate immunity, normally mediated by Il-17 and Il-22, increases the susceptibility to OPC in these Tg mice

Analyse de la réponse macrophagique au Candida albicans chez la souris transgénique exprimant le génome du VIH-1

La candidose oro-pharyngée (COP) est l’infection opportuniste la plus répandue chez les patients infectés au VIH-1. Un modèle de COP chez la souris transgénique (Tg) exprimant une partie du génome du VIH-1 (CD4C/HIVMutA) est maintenant disponible. Grâce à ce modèle, il est possible d’étudier les perturbations quantitatives et fonctionnelles des macrophages exprimant les gènes nef, rev et env du VIH-1 dans le contexte d’une COP. Cette étude démontre que la présence du transgène n’influence pas le pourcentage des macrophages dans la muqueuse buccale et le petit intestin, malgré le fait que la charge buccale de C. albicans soit significativement plus élevée chez les souris Tg. Cependant, l’expression du transgène cause une diminution de la production de H2O2 par les macrophages, ainsi que l’augmentation de la production de la cytokine proinflammatoire IL-6 et de la chimiokine MCP-1.Oro-pharyngeal candidiasis (OPC) is the most common opportunistic infection in HIV-1 infected patients. An OPC model using transgenic mice (CD4C/HIVMutA) expressing selected genes of the HIV-1 genome is now available. Using this model, it is now possible to study potential quantitative and functional disturbances in macrophages expressing the nef, rev and env genes of HIV-1 in the context of OPC. This study shows that transgene expression does not affect quantitative percentage values of macrophages in the oral mucosa and the small intestine, although burdens of C. albicans loads are increased in Tg mice. Transgene expression does induce diminished H2O2 production in macrophages, while increasing production of the proinflammatory cytokine IL-6 and the chemokine MCP-1

Metastable states of a flux line lattice studied by transport and Small Angle Neutron Scattering

Flux Lines Lattice (FLL) states have been studied using transport measurements and Small Angle Neutron Scattering in low T$_c$ materials. In Pb-In, the bulk dislocations in the FLL do not influence the transport properties. In Fe doped NbSe$_{2}$, transport properties can differ after a Field Cooling (FC) or a Zero Field Cooling (ZFC) procedure, as previously reported. The ZFC FLL is found ordered with narrow Bragg Peaks and is linked to a linear V(I) curve and to a superficial critical current. The FC FLL pattern exhibits two Bragg peaks and the corresponding V(I) curve shows a S-shape. This can be explained by the coexistence of two ordered FLL slightly tilted from the applied field direction by different superficial currents. These currents are wiped out when the transport current is increased.Comment: accepted for publication in Phys. Rev.

Comment to the paper : Collapse of the vortex-lattice inductance and shear modulus at the melting transition in untwinned YBa2_2Cu3_3O7_7, by Matl \QTR{em}{et al.}

In a recent paper, Matl et al present a high-frequency study of the complex resistivity of a pinned vortex lattice in YBaCuO . They focus on the inductive-to-resistive transition which is investigated as a function of temperature at a constant field $B_0=2$ T, so that the transition is associated with the vanishing of vortex pinning strength. To our view, their conclusions rely on a rather brittle experimental body and the collapse of C66 results from an involved analysis of the finite frequency corrections to $\rho (\omega)$. These corrections are not necessary since the complex frequency spectrum has been previously interpreted by the two modes model, first proposed for low Tc materials. We think that it is more adequate to interpret the present data and should be at least considered.Comment: 4pages tex. submitted to PR

Persistence of characteristics of an ordered flux line lattice above the second peak in Bi2Sr2CaCu2O8+δBi_2Sr_2CaCu_2O_{8+ \delta}

We report Small Angle Neutron Scattering measurements of the flux lines lattice (FLL) in $Bi_2Sr_2CaCu_2O_{8+ \delta}$. As previously reported, the scattered intensity decreases strongly when the magnetic field is increased, but it remains measurable far above the second peak. The direct observation of Bragg peaks proves that the characteristics of a lattice are still present. No structural features related to a symmetry breaking, such as a liquid like or an amorphous state, can be observed. However, the associated scattered intensity is very low and is difficult to explain. We discuss the coexistence between two FLL states as a possible interpretation.Comment: accepted for publication in Phys Rev

Why pinning by surface irregularities can explain the peak effect in transport properties and neutron diffraction results in NbSe2 and Bi-2212 crystals?

The existence of a peak effect in transport properties (a maximum of the critical current as function of magnetic field) is a well-known but still intriguing feature of type II superconductors such as NbSe2 and Bi-2212. Using a model of pinning by surface irregularities in anisotropic superconductors, we have developed a calculation of the critical current which allows estimating quantitatively the critical current in both the high critical current phase and in the low critical current phase. The only adjustable parameter of this model is the angle of the vortices at the surface. The agreement between the measurements and the model is really very impressive. In this framework, the anomalous dynamical properties close to the peak effect is due to co-existence of two different vortex states with different critical currents. Recent neutron diffraction data in NbSe2 crystals in presence of transport current support this point of view

Distribution of Transport Current in a Type II Superconductor Studied by Small Angle Neutron Scattering

We report Small-Angle Neutron Scattering (SANS) measurements on the vortex lattice in a PbIn polycrystal in the presence of an applied current. Using the rocking curves as a probe of the distribution of current in the sample, we observe that vortex pinning is due to the surface roughness. This leads to a surface current that persists in the flux flow region. We show the influence of surface treatments on the distribution of this current.Comment: 5 pages 5 figures. accepted for publication in Phys Rev Let

The Colocalization Potential of HIV-Specific CD8+ and CD4+ T-Cells is Mediated by Integrin β7 but Not CCR6 and Regulated by Retinoic Acid

CD4+ T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8+ and CD4+ T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a “signature” for HIV-specific but not CMV-specific CD4+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4+ versus CD8+ T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8+ T-cells may colocalize in excess with CD4+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6+CD4+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8+ T-cells to migrate in the vicinity of CCR6+CD4+ T-cells may facilitate HIV replication and dissemination at mucosal sites

Oropharyngeal Candidiasis in HIV Infection: Analysis of Impaired Mucosal Immune Response to Candida albicans in Mice Expressing the HIV-1 Transgene

IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in transgenic mice expressing the genome of HIV-1 in immune cells and displaying an AIDS-like disease. Defective IL-17 and IL-22-dependent mucosal responses to C. albicans were found to determine susceptibility to OPC in these transgenic mice. Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs. CD8+ T-cells recruited to the oral mucosa of the transgenic mice limited the proliferation of C. albicans in these conditions of CD4+ T-cell deficiency. Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination

Persistence of an ordered flux line lattice above the second peak in Bi2Sr2CaCu2O8+

We report small angle neutron scattering measurements of the flux lines lattice (FLL) in Bi2Sr2CaCu2O8+. As previously reported, the scattered intensity decreases strongly when the magnetic field is increased, but it remains measurable far above the second peak. The direct observation of Bragg peaks proves that the characteristics of a lattice are still present. No structural features related to a symmetry breaking, such as a liquidlike or an amorphous state, can be observed. However, the associated scattered intensity is very low and is difficult to explain. We discuss the coexistence between two FLL states as a possible interpretation