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Biomedical subjects

R M Zinkernagel

Publications and source records attributed to R M Zinkernagel.

At least 19 recordsLinked to original sources
PubMed1992

Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen.

The basis of antiviral protection by memory cytotoxic T lymphocytes (CTL) was investigated in vivo and in vitro using lymphocytic choriomeningitis virus (LCMV) and recombinant vaccinia viruses expressing the LCMV-glycoprotein (vacc-GP) or -nucleoprotein (vacc-NP). The widely replicating LCMV with a tendency to persist induced solid long-term protective memory. The poorly replicating vaccinia recombinant viruses revealed in the vaccinated host that the antiviral capacity of the secondary immune T cell response and the protection against lethal LCM was dependent upon the immunizing antigen and its dose. Protection against lethal choriomeningitis is less sensitive to assess memory because it depends upon high levels of CTL precursors (p) and/or on an activated state of memory CTL. In contrast, antiviral protection measured as the capacity of the primed host to reduce virus titers after challenge infection correlated with elevated CTLp frequencies after immunization with live LCMV or recombinant vaccinia virus-expressing the major LCMV epitope. CTLp frequencies were constantly increased up to 70 d for LCMV immune mice, but rapidly decreased a few weeks after immunization with low dose vaccinia recombinant virus. For example, mice primed with 2 x 10(6) plaque-forming units (PFU) of vacc-NP, or 2 x 10(2) PFU, or 2 x 10(6) PFU of vacc-GP were antivirally protected on day 7 but not after day 30 when CTLp could not be measured any longer in vitro. However, greater priming doses of vacc-NP (10(4) or 2 x 10(6) PFU) as well as LCMV (2 x 10(2) PFU) induced elevated levels of CTLp and antiviral protection for 60 d or longer. Adoptive transfer experiments of immune spleen cells into syngeneic recipients without addition of antigen demonstrated that maintenance of the antiviral protective capacity of the transferred cells depended on the presence of viral antigen. Thus, antiviral protection by memory CTL may be rather short-lived since it is based on activated T cells continuously stimulated by persisting antigen. This is best achieved by high immunizing antigen doses yielded either by widely replicating viruses or high doses of poorly replicating recombinant vaccines.

Animals↗
PubMed1992

Skin test to assess virus-specific cytotoxic T-cell activity.

A way to assess specific CD8+ T-cell activity in a skin test analogous to the conventional delayed-type hypersensitivity (DTH) reaction for CD4+ T cells is presented. Local injection of viral class I binding peptides caused a specific CD8+ T-cell-mediated DTH in footpads of virally infected mice. The DTH was inducible only during the acute phase of the infection. Apparently because of the short half-life of locally available peptide, only activated CD8+ effector T cells could mediate the reaction. This skin test may prove to be particularly interesting for use in humans to evaluate the activation status of CD8+ T cells during acute viral infections and of memory CD8+ T cells, for example, in chronically active immunopathological disease or infection.

Animals↗
PubMed1992

Extrathymic positive selection of alpha beta T-cell precursors in nude mice.

T lymphocytes expressing alpha beta T-cell receptors with sufficient affinity to major histocompatibility complex (MHC) molecules expressed on thymus epithelial cells are positively selected and mature to functional T cells. But several studies have demonstrated that athymic nude mice grafted with MHC-incompatible thymuses developed T cells specific for nude host rather than thymic MHC. We examined this paradox by analysing the specificity of T lymphocytes derived from nude mice. We report here that nude T lymphocyte precursors transferred to allogeneic SCID (severe combined immunodeficiency) mice with a functioning thymus (but lacking T or B cells) generated host MHC-restricted effector T cells but also contained T cells restricted to donor MHC. If nude T cells were depleted from nude lymphohaemopoietic donor cells before or after transfer, only host MHC-specific T cells matured. The results may explain the unusual MHC specificities of nude T lymphocytes described in earlier studies and demonstrate two separate differentiation steps: in nude mice, T cells may be positively selected for self-MHC restriction specificity extrathymically; then a functional thymus is required for efficient T cell maturation.

Animals↗
PubMed1992

Preferential positive selection of V alpha 2+ CD8+ T cells in mouse strains expressing both H-2k and T cell receptor V alpha a haplotypes: determination with a V alpha 2-specific monoclonal antibody.

A monoclonal antibody, B20.1, was generated by fusing spleen cells from a Lou rat immunized with a soluble alpha/beta T cell receptor (TcR; V alpha 2/V beta 2) to mouse myeloma cells. Analysis of a panel of V alpha 2 mRNA-expressing T cell lines, hybridomas and transfectants revealed that the B20.1 antibody was specific for murine TcR V alpha 2 chains. The V alpha 2+ T cell population was examined in various inbred strains by two-color immunofluorescence using B20.1 and CD4- and CD8-specific antibodies with the following results: (a) the B20.1 antibody detected most members of the TcR V alpha 2 subfamily in the four TcR V alpha haplotypes tested; (b) in most strains examined, TcR V alpha 2 expression was biased to the CD4 subset (7.4%-17.4% V alpha 2+ T cells) as compared to the CD8 compartment (3.8%-13.3%); (c) TcR V alpha 2 expression was not influenced by Mls gene products and (d) increased positive selection of V alpha 2+ CD8+ T cells by H-2k major histocompatibility complex molecules occurred in all murine strains tested of the TcR V alpha a, but not in those bearing the TcR V alpha b haplotype.

Animals↗
PubMed1992

Vaccination or tolerance to prevent diabetes.

Experiments with transgenic mice expressing the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promoter (RIP) have demonstrated that potentially self-reactive T cells that normally ignore self peptides may nevertheless be induced by self peptides or "cross-reactive" foreign (e.g. viral) peptides that arise in the host in an immunogenic form; once activated these potentially self-reactive T cells may cause autoaggressive diseases (e.g. diabetes). The possibility of vaccinating against such T cell-mediated immunopathological diseases was evaluated in the RIP-GP transgenic mouse line Bln. Any attempt to vaccinate with the self antigen itself (e.g. recombinant vaccinia virus expressing LCMV-GP) failed to protect mice from disease. However, immunization with a recombinant vaccinia virus expressing LCMV-nucleoprotein (vacc-NP) as a non-GP LCMV vaccine was able to modulate the immune response and prevented autoaggressive disease in a MHC-dependent fashion. In contrast, tolerance induction neonatally or, more generally applicable, by lethal irradiation and reconstitution with neo-self antigen-expressing bone marrow cells always resulted in prevention of virally induced diabetes in this model situation.

Animals↗
PubMed1992

T cells causing immunological disease.

Evidence is summarized that genetically encoded self peptides may not be considered immunological as self when expressed solely extrathymically on non-lymphohemopoietic cells; nevertheless, they are antigenic and are recognized by induced effector T cells. An immune response is readily induced against such "nonimmunological" self (as against foreign) by an appropriate presentation of these self peptides on proper antigen-presenting cells. If it is substantial, such an immune response causes a disease resembling an autoimmune disease, which is more appropriately called an "immunopathological T cell-mediated disease" rather than a T cell autoimmunity. These pathogenetic considerations may be incorporated into a revised-extended Gell and Coomb's classification of immunopathologies. If this view of immunopathological T cell-mediated diseases against nonimmunological self is correct, such diseases should be amenable to the same prevention (i.e., vaccination) and treatment principles, as are T cell immune responses to foreign antigens.

Animals↗
PubMed1992

Virus-induced acquired immune suppression by cytotoxic T cell-mediated immunopathology.

Acute infection with lymphocytic choriomeningitis virus causes a severe immune suppression in immunocompetent mice by triggering a T cell-mediated immunopathology, probably directed against infected macrophages and dendritic cells. An important role of gamma interferon may be to protect lymphohaemopoietic cells from virus infection and destruction by cytopathic effects of either the virus or of anti-viral immunity.

Animals↗
PubMed1992

Virally induced immunosuppression.

A mouse model of virus-triggered, T-cell mediated acquired immunosuppression is analyzed. Lymphocytic choriomeningitis virus initially infects mostly macrophages and antigen-presenting cells; these are destroyed by lymphocytic choriomeningitis virus specific cytotoxic T cells resulting in immunosuppression. Similar immunopathological mechanisms may play a role in acquired immune deficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Vaccination with a synthetic peptide modulates lymphocytic choriomeningitis virus-mediated immunopathology.

Vaccination with a nucleopeptide (NP 118; amino acids 118 to 132) representing a cytotoxic T-cell epitope of lymphocytic choriomeningitis virus (LCMV) can modulate immunopathology. Immunization with NP 118 protected H-2d mice against intracerebral infection with the LCMV-ARMSTRONG isolate. However, when NP 118-primed H-2d mice were challenged intracerebrally with an intermediate dose (5 x 10(4) PFU) of the LCMV-DOCILE strain, all mice primed with NP 118 emulsified in incomplete Freund's adjuvant died, whereas unprimed mice survived. Correspondingly, peptide vaccination enhanced specifically the cytotoxic T-cell response, influencing the critical balance between T-cell response and virus spread.

Animals↗
PubMed1979

Thymic reconstitution of nude F1 mice with one or both parental thymus grafts.

Thymus-derived lymphocytes (T cells) have two outstanding characteristics that distinguish them from other lymphocytes: (a) they express two specificities, one for self-antigens, the major transplantation antigens (H) coded by the major histocompatibility gene complex (MHC), and a second specificity for foreign antigenic determinants. (b) T cells must undergo differentiation or maturation in the thymus (1, 2). Apparently, an important step in T-cell differentiation in the thymus is the selection of T-cells' restriction specificity for self-H. This interpretation stems from experiments with chimeras formed by lethally irradiating parental type mice and reconstituting them with F(1) stem cells: the maturing F(1) T cells expressed predominantly the restriction specificities for the recipient parental MHC type (3-8). Alternatively, adult F(1) mice that were thymectomized, lethally irradiated, reconstituted with bone marrow, and then engrafted with a parental thymus had T cells that were restricted predominantly to the thymus donors' H-2 (4-8). The present study first extends these observations to nude mice that are born without a thymus and therefore do not develop functional T cells and second, attempts to study the possibility that suppression may be responsible for the apparent influence of the radioresistant portion of the thymus on T- cell restriction specificities. We tested the immunocompetence and restriction specificities expressed by lymphocytes from F(1) nude mice reconstituted with both parental thymus grafts; our expectation was that suppression of the expression of T-cell restriction specificity should result either in complete immunoincompetence or emergence of only one of the two possible sets of restriction specificities. Nude F(1)mice that simultaneously received thymus gratis from both parents developed spleen cells restricted to both parental H-2 types. These results are compatible with the idea that the thymus' influence on T- cell restriction is via positive selection rather than by suppression.

Animals↗
PubMed1979

Selective and unidirectional membrane redistribution of an H-2 antigen with an antibody-clustered viral antigen: relationship to mechanisms of cytotoxic T-cell interactions.

We have studied the co-redistribution of vesicular stomatitis virus (VSV) antigen and of individual H-2 antigens on the surfaces of mouse cells, and in parallel we have also used these VSV-infected cells as targets in cytotoxic T-cell killing experiments. Antibody-induced patching and capping of the VSV antigen caused an extensive co-patching and co-capping of the H-2Kb antigen but not of the H-2Db antigen. In reciprocal experiments, the antibody-induced patching of the H-2Kb or H-2Db antigen did not result in a co-patching of the VSV antigen. Radioimmunoassays showed that the relative numbers of H-2Kb, H-2Db, and VSV antigens on the surfaces of the cells exhibiting such nonreciprocal co-redistributions were closely similar. Furthermore, the H-2 restricted cytotoxic T-cell lysis of these target cells showed a marked preference for H-2Kb compared to H-2Db compatibility. We propose that the VSV and H-2 antigens are molecularly independent entities in the unpreturbed target cell membrane but that the antibody-induced clustering of the VSV antigen causes a selective and unidirectional co-redistribution (which we designate as syn-capping) of H-2Kb with the VSV antigen clusters. It is suggested that such a T-cell-induced syn-capping process involving an antigen and an H-2 molecule on the target cell may play a critical role in the mechanism of cytotoxic T-cell killing.

Antibodies, Viral↗