Cell-Mediated Immunity to Mouse Adenovirus Infection

Migration of peritoneal exudate cells (PEC), which were prepared from mice immunized against mouse adenovirus (M-Ad), was inhibited upon exposure to the antigenic extract of M-Ad-infected cells. This inhibition was shown to be blocked when infected cells or their extracts were pretreated with antiserum against M-Ad-induced cell surface(s) antigen(s) or with antisera against alloantigens of infected cells. Immune spleen cell-mediated cytolysis of M-Ad-infected cells was also blocked in the presence of anti-S, anti-alloantigen or anti-β₂m serum. Immunofluorescent antibody staining of S antigen(s) was blocked when infected cells were pretreated with anti-alloantigen or anti-β₂m serum, whereas it was not blocked when they were pretreated with anti-mouse immunoglobulin or anti-Thy-1.2 serum. Conversely, immunofluoresent antibody staining of alloantigens was blocked when infected cells were pretreated with anti-S serum. These findings indicate that S and alloantigens are associated with each other or at least located very close to each other.     

Host Genetic Background Influences the Response to the Opportunistic Pseudomonas aeruginosa Infection Altering Cell-Mediated Immunity and Bacterial Replication

Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream, urinary tract, and surgical site infections. The clinical outcome of P. aeruginosa infections may be extremely variable among individuals at risk and patients affected by cystic fibrosis. However, risk factors for P. aeruginosa infection remain largely unknown. To identify and track the host factors influencing P. aeruginosa lung infections, inbred immunocompetent mouse strains were screened in a pneumonia model system. A/J, BALB/cJ, BALB/cAnNCrl, BALB/cByJ, C3H/HeOuJ, C57BL/6J, C57BL/6NCrl, DBA/2J, and 129S2/SvPasCRL mice were infected with P. aeruginosa clinical strain and monitored for body weight and mortality up to seven days. The most deviant survival phenotypes were observed for A/J, 129S2/SvPasCRL and DBA/2J showing high susceptibility while BALB/cAnNCrl and C3H/HeOuJ showing more resistance to P. aeruginosa infection. Next, one of the most susceptible and resistant mouse strains were characterized for their deviant clinical and immunological phenotype by scoring bacterial count, cell-mediated immunity, cytokines and chemokines profile and lung pathology in an early time course. Susceptible A/J mice showed significantly higher bacterial burden, higher cytokines and chemokines levels but lower leukocyte recruitment, particularly neutrophils, when compared to C3H/HeOuJ resistant mice. Pathologic scores showed lower inflammatory severity, reduced intraluminal and interstitial inflammation extent, bronchial and parenchymal involvement and diminished alveolar damage in the lungs of A/J when compared to C3H/HeOuJ. Our findings indicate that during an early phase of infection a prompt inflammatory response in the airways set the conditions for a non-permissive environment to P. aeruginosa replication and lock the spread to other organs. Host gene(s) may have a role in the reduction of cell-mediated immunity playing a critical role in the control of P. aeruginosa infection. These results now provide a basis for mapping genomic regions underlying host susceptibility to P. aeruginosa infection.     

病毒感染和免疫清除中的C型凝集素

树突状细胞和朗罕氏细胞是人体防御病毒入侵的第一道屏障,这些细胞表达的C型凝集素对于细胞发挥抗原免疫清除和细胞之间的黏附有重要作用。其中DC—SIGN和DC—SIGNR在HIV等多种病毒的感染中发挥重要作用。随着基因组学的发展鉴定了许多新的C型凝集素,它们在免疫清除和病毒感染中都可能发挥重要作用。     

Bactericidal Immunity to Salmonella in Africans and Mechanisms Causing Its Failure in HIV Infection

Background

Nontyphoidal strains of Salmonella are a leading cause of death among HIV-infected Africans. Antibody-induced complement-mediated killing protects healthy Africans against Salmonella, but increased levels of anti-lipopolysaccharide (LPS) antibodies in some HIV-infected African adults block this killing. The objective was to understand how these high levels of anti-LPS antibodies interfere with the killing of Salmonella.

Methodology/Principal Findings

Sera and affinity-purified antibodies from African HIV-infected adults that failed to kill invasive S. Typhimurium {"type":"entrez-nucleotide","attrs":{"text":"D23580","term_id":"427513","term_text":"D23580"}}D23580 were compared to sera from HIV-uninfected and HIV-infected subjects with bactericidal activity. The failure of sera from certain HIV-infected subjects to kill Salmonella was found to be due to an inherent inhibitory effect of anti-LPS antibodies. This inhibition was concentration-dependent and strongly associated with IgA and IgG2 anti-LPS antibodies (p<0.0001 for both). IgG anti-LPS antibodies, from sera of HIV-infected individuals that inhibit killing at high concentration, induced killing when diluted. Conversely, IgG, from sera of HIV-uninfected adults that induce killing, inhibited killing when concentrated. IgM anti-LPS antibodies from all subjects also induced Salmonella killing. Finally, the inhibitory effect of high concentrations of anti-LPS antibodies is seen with IgM as well as IgG and IgA. No correlation was found between affinity or avidity, or complement deposition or consumption, and inhibition of killing.

Conclusion/Significance

IgG and IgM classes of anti-S. Typhimurium LPS antibodies from HIV-infected and HIV-uninfected individuals are bactericidal, while at very high concentrations, anti-LPS antibodies of all classes inhibit in vitro killing of Salmonella. This could be due to a variety of mechanisms relating to the poor ability of IgA and IgG2 to activate complement, and deposition of complement at sites where it cannot insert in the bacterial membrane. Vaccine trials are required to understand the significance of lack of in vitro killing by anti-LPS antibodies from a minority of HIV-infected individuals with impaired immune homeostasis.     

Th17细胞在肺部感染免疫中的作用

Th17细胞是近年来发现的一种新的效应T细胞亚群,在自身免疫性疾病和感染中发挥重要的作用,其分泌产生几种致炎细胞因子,包括新发现的细胞因子白细胞介素17。Th17产生的细胞因子与Th1、Th2不同并且与其相互对抗。Th17细胞很可能对防御胞外病原菌的感染及自身免疫性疾病产生影响。综述了Th17细胞产生的细胞因子及其在肺部感染免疫中的作用相关方面的进展。     

Ontogeny of Cell-Mediated Immunity of Murine Thymocytes and Spleen Cells

The ontogeny of cell-mediated immunity of spleen cells and thymocytes from B10 mice was studied in both in vitro mixed leukocyte culture and cell-mediated lympholysis reactions. Results show that newborn spleens contain cells competent to respond to X-irradiated allogeneic spleen cells in mixed leukocyte culture. The mixed leukocyte culture response of spleen cells, in terms of both index of stimulation and increment of tritiated thymidine incorporation, seems to be higher for mice four weeks or older than for mice less than four weeks old. The cell-mediated lympholysis response of spleen cells is not detectable until two days postpartum. It reaches adult levels in terms of % cytolysis by day four after birth. Thus, the transition period of the ontogeny of cell-mediated lympholysis response of spleen cells is apparently 0–4 days of age.
Newborn and early postnatal thymocytes (0–7 days of age) respond in mixed leukocyte culture at least as strongly as adult thymocytes (2–3 months of age). The cell-mediated lympholysis response of thymocytes is already detectable at birth, but weaker in terms of % cytolysis when compared with the cell-mediated lympholysis response of thymocytes from two days to six weeks of age. The cell-mediated lympholysis response of thymocytes starts to decline at 6–8 weeks of age. Thus, around the time of birth, there is a transition period in the cell-mediated lympholysis response of thymocytes during which thymocytes start to show high cell-mediated lympholysis reactivity. There is a second transition period between six and eight weeks of age during which the cell-mediated lympholysis response of thymocytes diminishes. The early, as well as late, postnatal cell-mediated lympholysis response of both spleen cells and thymocytes seems to be specific in nature.     

类泛素蛋白ISG15及其在先天免疫中的作用

病毒感染和干扰素刺激高等动物细胞,均可以强烈地诱导表达干扰素刺激基因15编码的蛋白ISG15,它是最早发现的类泛素修饰蛋白.虽然针对泛素及其修饰功能已进行了广泛而深入地研究,但对于ISG15共价修饰以及它的生物学功能了解甚少,有待进一步探讨.该领域的研究近几年有所突破,发现了有关ISG15修饰的酶系统,ISG15及其修饰系统在先天免疫以及干扰素信号调节中的重要作用.简要介绍ISG15的发现历史、生化性质、基因调控特点以及ISG15修饰系统中所涉及的酶,总结目前研究ISG15及其修饰与调节先天性免疫相关过程的一些最新进展.     

Suppression of Cell-Mediated Immunity following Recognition of Phagosome-Confined Bacteria

Listeria monocytogenes is a facultative intracellular pathogen capable of inducing a robust cell-mediated immune response to sub-lethal infection. The capacity of L. monocytogenes to escape from the phagosome and enter the host cell cytosol is paramount for the induction of long-lived CD8 T cell–mediated protective immunity. Here, we show that the impaired T cell response to L. monocytogenes confined within a phagosome is not merely a consequence of inefficient antigen presentation, but is the result of direct suppression of the adaptive response. This suppression limited not only the adaptive response to vacuole-confined L. monocytogenes, but negated the response to bacteria within the cytosol. Co-infection with phagosome-confined and cytosolic L. monocytogenes prevented the generation of acquired immunity and limited expansion of antigen-specific T cells relative to the cytosolic L. monocytogenes strain alone. Bacteria confined to a phagosome suppressed the production of pro-inflammatory cytokines and led to the rapid MyD88-dependent production of IL-10. Blockade of the IL-10 receptor or the absence of MyD88 during primary infection restored protective immunity. Our studies demonstrate that the presence of microbes within a phagosome can directly impact the innate and adaptive immune response by antagonizing the signaling pathways necessary for inflammation and the generation of protective CD8 T cells.     

STING-Dependent Type I IFN Production Inhibits Cell-Mediated Immunity to Listeria monocytogenes

Infection with Listeria monocytogenes strains that enter the host cell cytosol leads to a robust cytotoxic T cell response resulting in long-lived cell-mediated immunity (CMI). Upon entry into the cytosol, L. monocytogenes secretes cyclic diadenosine monophosphate (c-di-AMP) which activates the innate immune sensor STING leading to the expression of IFN-β and co-regulated genes. In this study, we examined the role of STING in the development of protective CMI to L. monocytogenes. Mice deficient for STING or its downstream effector IRF3 restricted a secondary lethal challenge with L. monocytogenes and exhibited enhanced immunity that was MyD88-independent. Conversely, enhancing STING activation during immunization by co-administration of c-di-AMP or by infection with a L. monocytogenes mutant that secretes elevated levels of c-di-AMP resulted in decreased protective immunity that was largely dependent on the type I interferon receptor. These data suggest that L. monocytogenes activation of STING downregulates CMI by induction of type I interferon.     

Evaluation of the Induction of Cell-Mediated Immunity Against Candida albicans in a Model of Cutaneous Infection in Newborn 0-Day-Old Mice

Mycopathologia - Candida albicans is a commensal fungus of the skin and mucous membranes in humans, but it is also responsible for mucocutaneous and systemic infections in immunocompromised...     

Neo-Lymphoid Aggregates in the Adult Liver Can Initiate Potent Cell-Mediated Immunity

Subcutaneous immunization delivers antigen (Ag) to local Ag-presenting cells that subsequently migrate into draining lymph nodes (LNs). There, they initiate the activation and expansion of lymphocytes specific for their cognate Ag. In mammals, the structural environment of secondary lymphoid tissues (SLTs) is considered essential for the initiation of adaptive immunity. Nevertheless, cold-blooded vertebrates can initiate potent systemic immune responses even though they lack conventional SLTs. The emergence of lymph nodes provided mammals with drastically improved affinity maturation of B cells. Here, we combine the use of different strains of alymphoplastic mice and T cell migration mutants with an experimental paradigm in which the site of Ag delivery is distant from the site of priming and inflammation. We demonstrate that in mammals, SLTs serve primarily B cell priming and affinity maturation, whereas the induction of T cell-driven immune responses can occur outside of SLTs. We found that mice lacking conventional SLTs generate productive systemic CD4- as well as CD8-mediated responses, even under conditions in which draining LNs are considered compulsory for the initiation of adaptive immunity. We describe an alternative pathway for the induction of cell-mediated immunity (CMI), in which Ag-presenting cells sample Ag and migrate into the liver where they induce neo-lymphoid aggregates. These structures are insufficient to support antibody affinity maturation and class switching, but provide a novel surrogate environment for the initiation of CMI.