Cytokines regulate lymphocyte development and differentiation, but precisely how they control these processes is still poorly tei understood. By using microarray technology to detect cytokine- G' induced genes, we identified a cDNA encoding Cybr, which was cel increased markedly in cells incubated with IL-2 and IL-12. The sci mRNA was most abundant in hematopoietic cells and tissues. The a predicted amino acid sequence is similar to that of GRP-1-associ- ad ated protein (GRASP), a recently identified retinoic acid-induced wa cytohesin-binding protein. Physical interaction, dependent on the by coiled-coil domains of Cybr and cytohesin-1, was demonstrated by m] coimmunoprecipitation of the overexpressed proteins from 293T ce cells. Cytohesin-1, in addition to its role in cell adhesion, is a pr guanine nucleotide-exchange protein activator of ARF GTPases. an Acceleration of guanosine 5'-O-(thiotriphosphate) binding to ARF by cytohesin-1 in vitro was enhanced by Cybr. Because the binding pr protein modified activation of ADP ribosylation factor by cytohe- m sin-1, we designate this cytokine-inducible protein Cybr (cytohesin lnl binder and regulator). pr

According to the current paradigm, lymphocyte homing to the small intestine requires the expression of two tissue-specific homing receptors, the integrin α4β7 and the CCL25 receptor CCR9. In this study, we investigated the organ distribution and the homing molecule expression of IgA Ab-secreting cells (ASCs) induced by intrarectal immunization with a particulate Ag, in comparison with other mucosal immunization routes. Intrarectal immunization induces gut-homing IgA ASCs that localize not only in the colon but also in the small intestine, although they are not responsive to CCL25, unlike IgA ASCs induced by oral immunization. The mucosal epithelial chemokine CCL28, known to attract all IgA ASCs, does not compensate for the lack of CCL25 responsiveness, because the number of Ag-specific cells is not decreased in the gut of CCR10-deficient mice immunized by the intrarectal route. However, Ag-specific IgA ASCs induced by intrarectal immunization express the integrin α4β7, and their number is considerably decreased in the gut of β7-deficient mice immunized by the intrarectal route, indicating that α4β7 enables these cells to migrate into the small intestine, even without CCL25 responsiveness. In contrast, IgA ASCs induced by intranasal immunization express low α4β7 levels and are usually excluded from the gut. Paradoxically, after intranasal immunization, Ag-specific IgA ASCs are significantly increased in the small intestine of β7-deficient mice, demonstrating that lymphocyte homing is a competitive process and that integrin α4β7 determines not only the intestinal tropism of IgA ASCs elicited in GALTs but also the intestinal exclusion of lymphocytes primed in other inductive sites.

ABSTRACT Murine norovirus (MNV) was used as a surrogate to study resistance of human norovirus to disinfectants used in hospitals. MNV was sensitive to alcohol, alcohol hand rubs, bleach, and povidone iodine-based disinfectant. Real-time reverse transcription-PCR results indicated that the presence of viral RNA did not correlate with the presence of infectious virus.

ABSTRACT Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.

Les rotavirus sont responsables d'un grand nombre de gastroenterites que les progres de l'hygiene n'ont pas reussi a reduire. Cependant, dans les pays developpes le probleme de ces episodes diarrheiques est surtout represente par leur cout financier, alors que dans les pays en voies de developpement c'est la mortalite infantile causee par ces infections qui pose un probleme de sante publique prioritaire. Une meilleure connaissance des mecanismes de la diarrhee a rotavirus peut deboucher sur l'elaboration d'une therapeutique symptomatique, mais l'espoir de voir reduire la mortalite infantile repose avant tout sur une vaccination efficace. Deux vaccins parfaitement toleres seront prochainement disponibles, RotaRix® et RotaTeq®. Les essais cliniques sur une grande echelle ont montre leur efficacite sur les gastroenterites severes. Cependant, les rotavirus presentent une tres grande diversite antigenique et la barriere d'espece s'est revelee fragile. Le phenomene d'emergence observe dans plusieurs pays developpes avec la souche G9 pourrait eventuellement se reproduire avec une souche non controlee par la vaccination. Ce risque necessite une vigilance epidemiologique et virologique durant la vaccination.

ABSTRACTRotavirus (RV) is the main etiological agent of severe gastroenteritis in infants, and vaccination seems the most effective way to control the disease. Recombinant rotavirus-like particles composed of the viral protein 6 (VP6) and VP2 (2/6-VLPs) have been reported to induce protective immunity in mice when administered by the intranasal (i.n.) route. In this study, we show that administration of 2/6-VLPs by the intrarectal (i.r.) route together with either cholera toxin (CT) or a CpG-containing oligodeoxynucleotide as the adjuvant protects adult mice against RV infection. Moreover, when CT is used, RV shedding in animals immunized by the i.r. route is even reduced in comparison with that in animals immunized by the i.n. route. Humoral and cellular immune responses induced by these immunization protocols were analyzed. We found that although i.r. immunization with 2/6-VLPs induces lower RV-specific immunoglobulin G (IgG) and IgA levels in serum, intestinal anti-RV IgA production is higher in mice immunized by the i.r. route. Cellular immune response has been evaluated by measuring cytokine production by spleen and Peyer's patch cells (PPs) after ex vivo restimulation with RV. Mice immunized by the i.n. and i.r. routes display higher gamma interferon production in spleen and PPs, respectively. In conclusion, we demonstrate that i.r. immunization with 2/6-VLPs protects against RV infection in mice and is more efficient than i.n. immunization in inducing an anti-RV immune response in intestinal mucosa.

Previous reports have indicated that the administration of granulocyte colony-stimulating factor (G-CSF) decreases ex vivo tumor necrosis factor (TNF) production in humans. In this study, we report that daily pretreatment of mice with G-CSF for three days decreases ex vivo lipopolysaccharide (LPS)-induced TNF production in whole blood. Conversely, production of interleukin-10 (IL-10) and prostaglandin E-2 (PGE(2)) is increased. The inhibitory effect of G-CSF pretreatment on TNF production is partially reversed by addition of an anti-IL-10 antibody, and completely reversed by combined addition of anti-IL-10 antibody and the cyclooxygenase (COX) inhibitor, ketoprofen. These results suggest that G-CSF decreases TNF production in this experimental model by increasing production of IL-10 and PG(2), which are both known inhibitors of TNF production.

The differentiation of naive CD4+ T cells into subsets of T helper cells is a pivotal process with major implications for host defense and the pathogenesis of immune-mediated diseases. Though the basic paradigm was discovered more than 15 years ago, new discoveries continue to be made that offer fresh insights into the regulation of this process (1). T helper (TH)1 cells produce interferon (IFN)-γ, promoting cell-mediated immunity and control of intracellular pathogens. We now know that TH1 differentiation is regulated by transcription factors such as T-bet, Stat1, and Stat4, as well as cytokines such as IL-12, IL-23, IL-27, type I IFNs, and IFN-γ. In contrast, TH2 cells produce IL-4, which promotes allergic responses and is important in host defense against helminths. The transcription factors Stat6, GATA-3, c-Maf, NFATs, and the cytokine IL-4 promote TH2 differentiation. These key regulators of TH differentiation are the subject of this review.