Crystal-ball gazing--the future of immunological research viewed from the cutting edge.
Explore the source record for details and available documents.
Allergy and Immunology↗
Biomedical subjects
R Zinkernagel
Publications and source records attributed to R Zinkernagel.
Responses to Cohn's discussion on the Zinkernagel-Hengartner 'Credo 2004'.
Explore the source record for details and available documents.
Animals↗
Viral escape and the failure of cellular immune responses.
Explore the source record for details and available documents.
Acute Disease↗
IL-4 and IL-10 antagonize IL-12-mediated protection against acute vaccinia virus infection with a limited role of IFN-gamma and nitric oxide synthetase 2.
Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-gamma is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-gamma) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12-/- mice were far more susceptible than IFN-gamma-/- mice, and primary CTL responses against VV were absent in IL-12-/- mice but remained intact in IFN-gamma-/- mice. Both CD4+ and CD8+ T cells from IL-12-/- mice were unimpaired in IFN-gamma production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4-/- mice and, even more strikingly, in IL-10-/- mice, which both produced elevated levels of the proinflammatory cytokines IL-1alpha and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-gamma and show that IL-4 and IL-10 modulate host protective responses to VV.
Acute Disease↗
Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes.
This study describes the construction of soluble major histocompatibility complexes consisting of the mouse class I molecule, H-2Db, chemically biotinylated beta2 microglobulin and a peptide epitope derived from the glycoprotein (GP; amino acids 33-41) of lymphocytic choriomeningitis virus (LCMV). Tetrameric class I complexes, which were produced by mixing the class I complexes with phycoerythrin-labeled neutravidin, permitted direct analysis of virus-specific cytotoxic T lymphocytes (CTLs) by flow cytometry. This technique was validated by (a) staining CD8+ cells in the spleens of transgenic mice that express a T cell receptor (TCR) specific for H-2Db in association with peptide GP33-41, and (b) by staining virus-specific CTLs in the cerebrospinal fluid of C57BL/6 (B6) mice that had been infected intracranially with LCMV-DOCILE. Staining of spleen cells isolated from B6 mice revealed that up to 40% of CD8(+) T cells were GP33 tetramer+ during the initial phase of LCMV infection. In contrast, GP33 tetramers did not stain CD8+ T cells isolated from the spleens of B6 mice that had been infected 2 mo previously with LCMV above the background levels found in naive mice. The fate of virus-specific CTLs was analyzed during the acute phase of infection in mice challenged both intracranially and intravenously with a high or low dose of LCMV-DOCILE. The results of the study show that the outcome of infection by LCMV is determined by antigen load alone. Furthermore, the data indicate that deletion of virus-specific CTLs in the presence of excessive antigen is preceded by TCR downregulation and is dependent upon perforin.
Animals↗
Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+ T cells to cause immunopathology.
We studied the impact of various infectious and proinflammatory agents on the induction of peripheral T cell tolerance. Adoptive transfer of CD8+ T cells from lymphocytic choriomeningitis virus (LCMV) T cell receptor transgenic mice into LCMV antigen transgenic mice expressing the LCMV glycoprotein epitope (gp) 33-41 under control of a major histocompatibility complex class I promoter led to efficient induction of peripheral tolerance after a period of transient activation. If, however, the recipient mice were challenged with viral or bacterial infections or proinflammatory agents (lipopolysaccharide or Poly:IC) early after cell transfer, tolerance induction was prevented and instead, CD8+ T cell activation leading to vigorous expansion and generation of cytolytic activity ensued. This became manifest in significant immunopathology mainly involving destruction of the splenic architecture and lysis of antigen-expressing lymphocyte and macrophage populations. Important parameters involved in the activation of host-reactive T cells by nonspecific infectious agents included the presence, localization, and quantity of the specific transgene-encoded self-antigen; in contrast, CD4+ T cells were not required. In mice surviving the acute phase, the transferred CD8+ T cells persisted at high levels in an anergic state; they were unable to generate cytolytic activity in vitro or to control LCMV infection in vivo. These results impinge on our understanding of the role of infectious agents in graft verus host reactions towards minor histocompatibility antigens.
Animals↗
Hierarchies of antigen-specific cytotoxic T-cell responses.
Studies carried out using either mice or humans have shown that cytotoxic T-lymphocyte (CTL) responses to many different pathogenic organisms often comprise CTL specific for multiple class I-restricted peptide epitopes. Differences in the magnitude of epitope-specific CTL responses appear to arise mainly from differences in the expression level of the corresponding class I/peptide complex on the surface of the antigen-presenting cell. The size of the CTL response may be limited by the frequency and possibly by the affinity of specific CTL precursors in the naive T-cell pool. Thus, both the efficiency of antigen processing and the composition of the peripheral T-cell pool impose direct limitations on the extent of a T-cell response to a given peptide epitope. Studies of CTL hierarchies have resulted in the identification of immunodominant epitopes i.e. peptide epitopes which stimulate the largest number of specific CTL and which are therefore generally believed to offer the best level of protection against the pathogen from which they were derived. It is also thought that CTL responses to non-dominant epitopes mediate protection against pathogenic challenge. These ideas are considered here with respect to experimental data collected following infection of mice with lymphocytic choriomeningitis virus.
Animals↗
Immune surveillance and AIDS progression.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
A comparison of efficacy and specificity of three NK depleting antibodies.
This study compares in vivo efficacy and specificity of the three NK cell depleting antibodies anti-asialo GM1, anti-NK 1.1 and the recently described TM beta 1, which is directed against the interleukin-2 receptor beta chain. All three antibodies are equally efficacious as assessed by abolishing NK mediated cytolytic activity induced by a high dose virus infection or Poly IC against YAC-1 targets. Similarly, the generation of virus-specific cytotoxic T cells (CTL) was unimpaired after NK depletion in two different virus infections. However, if mice are treated with the antibodies several days after virus infection, when strong CTL responses have already been generated, anti-asialo GM1 and-to a lesser extent-also TM beta 1 have a significant effect on CTL activity. Only after treatment with anti-NK 1.1 antibody, CTL activity was not significantly impaired. We conclude, that of the NK depleting antibodies currently available, anti-NK 1.1 allows the best differentiation of activated CTL and NK cells in vivo.
Animals↗
Different susceptibility of cytotoxic T cells to CD95 (Fas/Apo-1) ligand-mediated cell death after activation in vitro versus in vivo.
To address the question of whether cytotoxic CD8+ T cells (CTL) activated in vivo are susceptible to cell death mediated by CD95 (Fas/Apo-1) ligand, a recombinant vaccinia virus expressing murine CD95L (vacc CD95L) was constructed, which drives CD95L expression to infected cells. T cells contacting virus-infected cells during priming, killing, or restimulation therefore encounter CD95L on the same cells. CD95L expression in vivo after infection with the vaccinia recombinant was sufficient to induce extensive necrosis in the liver of normal but not of CD95 mutant lpr mice. Fibroblast cell lines infected with this virus specifically killed CD95-transfected target cells and in vitro activated T cells. In contrast, when T cells were activated by a viral infection in vivo, they were not susceptible to CD95L-mediated cell death during the induction, effector, or memory phase in vitro or in vivo. These results suggest no direct role for CD95L in regulating CTL responses in vivo.
Animals↗
Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice.
To investigate the roles of tumor necrosis factor (TNF) and lymphotoxin (LT)-alpha in the development and function of the immune system, the Tnf and Ltalpha genes were simultaneously inactivated in mice by homologous recombination. These mutant mice are highly susceptible to Listeria monocytogenes infection and resistant to endotoxic shock induced by the combined administration of D-galactosamine (D-GaIN) and lipopolysaccharide (LPS). Their splenic microarchitecture is disorganized, characterized by the loss of the clearly defined marginal zone, ill defined T and B cell areas, and absence of MAdCAM-1 and reduced ICAM-1, VCAM-1 and Mac-1 expression. They are devoid of peripheral lymph nodes and Peyer's patches, and show a strong reduction of IgA+ plasma cells in the intestinal lamina propria. The alymphoplasia is accompanied by a marked B lymphocytosis and reduced basal lg levels. Ig depositions in the renal glomerulus and a strong up-regulation of MHC class I antigen expression on endothelial cells of different tissues are observed. The primary humoral immune response towards sheep red blood cells reveals a defective IgG isotype switch, while that against vesicular stomatitis virus is normal. The cytotoxic T cell responses are attenuated, although still effective, against vaccinia, lymphocytic choriomeningitis virus (LCMV-ARM) and LCMV-WE. In conclusion, the combined inactivation of Tnf and Ltalpha confirms their essential role in the normal development and function of the immune system.
Animals↗
Efficient immune responses in mice lacking N-region diversity.
Mice with a null mutation in the terminal deoxynucleotidyl transferase (TdT) gene harbor immunoglobulin and T cell receptor repertoires essentially devoid of N-region diversity. Consequently, the CDR3 loops important for antigen recognition are shorter and considerably less diverse than those of wild-type controls. We find surprisingly normal immune responses in TdT0 mice, as regards both efficiency and specificity. This provokes a reconsideration of the assumption that N-region diversity is required for an effective T and B cell repertoire.
Amino Acid Sequence↗
Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune response, acute-phase reaction and haematopoiesis (for reviews see refs 1, 2). In vitro, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and interleukin-11 display overlapping activities with IL-6. This functional redundancy may be explained by the interactions of specific binding receptors with a common signal-transducing receptor (gp130) (for reviews see refs 3, 4). To elucidate the unique function of IL-6 in vivo, we have disrupted the IL-6 gene by homologous recombination. IL-6-deficient mice develop normally. They fail to control efficiently vaccinia virus and infection with Listeria monocytogenes, a facultative intracellular bacterium. The T-cell-dependent antibody response against vesicular stomatitis virus is impaired. Further, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with lipopolysaccharide. We conclude that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
Acute-Phase Reaction↗
Severe immunodeficiency associated with a human immunodeficiency virus 1 NEF/3'-long terminal repeat transgene.
We have generated several transgenic mouse strains carrying a human immunodeficiency virus 1 (HIV-1) NEF/3' long terminal repeat (LTR) transgene under control of a T cell-specific promoter-enhancer element, showing a depletion of CD4+ T cells in the thymus and periphery. The immunological functions of the line with the most dramatic changes in lymphocyte populations, B6/338L, were analyzed in greater detail. The presence of the transgene in the heterozygous animal is associated with a dominant severe immunodeficiency. Older animals develop lymph-adenopathy and splenomegaly. CD4+CD8+ and CD4+CD8- single positive thymocytes already are depleted in these mice at the earliest stages in ontogeny, and peripheral T cells are reduced in frequency and present cell surface marker expression, which is characteristic for memory and activated T cells. The immunological response of B6/338L mice to several viral infections is also greatly impaired. Thus, the HIV-1 NEF/3' LTR as transgene in T cells can cause immunodeficiency and disease with striking similarities to a known retrovirus-induced immunodeficiency called murine AIDS (H. C. Morse III, S. K. Chattopadhyay, M. Makino, T. N. Frederickson, A. W. Hügin, and J. W. Hartley. 1992. AIDS. 6:607).
Aging↗
Virus or a hapten-carrier complex can activate autoreactive B cells by providing linked T help.
We investigated the mechanism leading to an IgG autoantibody response in two transgenic mouse lines expressing the glycoprotein of vesicular stomatitis virus (VSV-G). Previous experiments have shown that these animals do not mount a transgene-specific IgG response upon stimulation with purified VSV-G or infection with recombinant vaccinia virus expressing VSV-G. However, infection of VSV-G transgenic animals with wild-type vesicular stomatitis virus, serotype Indiana, readily induced VSV-G-specific, neutralizing IgG autoantibodies. We have tested whether this labile state of tolerance reflected differential availability of VSV-G-specific T help. For this, we immunized transgenic mice with the self-antigen VSV-G covalently coupled to sperm-whale myoglobulin (VSV-G-SWM), to provide new T helper epitopes that are linked to the B cell epitope; co-injected uncoupled VSV-G and SWM served as control. High titers of VSV-G specific IgG autoantibodies were detected in serum of mice immunized with VSV-G-SWM but not after co-injection of uncoupled VSV-G and SWM. Transgenic animals depleted of CD4+ T cells prior to injection of VSV-G-SWM failed to mount an IgG response. Priming of transgenic mice with the foreign carrier did not accelerate the IgG autoantibody response to VSV-G-SWM, suggesting that B cells were limiting the rate of the response. Thus, self-reactive B cells could be triggered to produce IgG, if they received linked T help specific for a foreign carrier determinant provided either by a classical carrier determinant or a virus.
Animals↗
[Virus-induced immune deficiency disease AIDS: direct pathogenic effect of the virus or immunopathology?].
Cytotoxic effectors-CD8+ T cells protect hosts against cytopathic viruses. CD8+ T cell mediated lysis of host cells infected with non-cytopathic viruses may lead to tissue disease causing damage as is the case in hepatitis B virus infections in men or lymphocytic choriomeningitis virus (LCMV) infections in mice. In a mouse model it was demonstrated that virus induced immunodeficiency by LCMV was not caused by the virus directly but rather by immunopathological consequences of anti-LCMV CD8+ T cells destroying LCMV-infected antigen-presenting cells and macrophages. These results may suggest that HIV induced immunodeficiency could similarly be caused by immunopathology because 1. HIV has not been demonstrated to be cytopathic in vivo. 2. CD8+ T cells control HIV infection efficiently for a longtime and 3. only few CD4+ T cells but many macrophages, monocytes and dendritic cells are productively HIV infected. Therefore AIDS may be the result of specific CD8+ T cells destroying antigen presenting cells and effector/macrophages/monocytes thereby causing immunosuppression and inability to control intracellular infections. Compared to the view that HIV is cytopathic, the immunopathological view of AIDS suggests obviously different vaccine and therapy strategies.
Acquired Immunodeficiency Syndrome↗
Phenotypic analysis of TNFR1-deficient mice and characterization of TNFR1-deficient fibroblasts in vitro.
In order to analyse the physiological relevance of the 55 kDa tumor necrosis factor receptor 1 (TNFR1) and its role in various TNF related pathological conditions, such as septic shock, we have generated mice by gene targeting deficient for TNFR1 expression. The TNFR1-deficient mice are unable to cope with Listeria monocytogenes infections but mount an apparently normal immune response when challenged with Vaccinia or LCMV viruses. They are resistant to the lethal effects of lipopolysaccharide (LPS) after sensitization with D-galactosamine (D-GalN) but remain sensitive to very high doses of LPS given alone. We have analyzed functions relevant to inflammatory processes, such as adhesion, secondary factor release, and proliferation in fibroblasts derived from these mice. We show that the TNFR1 virtually monopolises TNF-mediated signaling in all these situations and that the 75 kDa TNFR2 seems to be largely restricted to an accessory role, which is compatible with the previously established "ligand passing" hypothesis.
Alleles↗