Fewer protective cytotoxic T-cell epitopes than T-helper-cell epitopes on vesicular stomatitis virus.

Cytotoxic T-lymphocyte (CTL) and T-helper-cell responses in various mouse strains were monitored. Protective CTL responsiveness against three proteins of vesicular stomatitis virus was H-2 linked and inducible only in half of the 15 combinations tested (each of five H-2 haplotypes combined with each of three viral proteins), whereas biologically relevant T-helper-cell responses were inducible in all. This suggests that vesicular stomatitis virus exhibits more T-helper-cell than CTL epitopes.

Virus-specific cytotoxic T cell-mediated lysis of lymphocytes in vitro and in vivo.

Virus-specific CTL play a major role in early antiviral protection against lymphocytic choriomeningitis virus (LCMV). When mice are infected with high doses of certain LCMV isolates, the initiated CTL response may vanish before the virus is eliminated completely. To evaluate the possibility that this may be because of CTL lysing CTL, we studied the susceptibility to lysis of LCMV-specific CTL clones and of primary immune spleen cells in vitro and in vivo.

Nonimmunogenic tumor cells may efficiently restimulate tumor antigen-specific cytotoxic T cells.

Induction of immunity to a viral protein that had been transfected into a tumor cell line was studied. The nucleoprotein (NP) of vesicular stomatitis virus (VSV) was used as a model tumor-associated Ag after transfection into EL-4, and H-2b thymoma originating from C57BL/6 mice. The NP-transfected cell line (EL-4NP) was lysed by NP-specific CTL and was found to restimulate NP-specific CTL in vitro as efficiently as did VSV-infected macrophages.

T cell-dependent IFN-gamma exerts an antiviral effect in the central nervous system but not in peripheral solid organs.

The antiviral relevance of soluble mediators that may operate in the vicinity of virus specific effector T cells was investigated. Mice were immunized with vesicular stomatitis virus (VSV) wild type (wt) and subsequently challenged with a mixture of two vaccinia recombinant viruses, one expressing the nucleoprotein of VSV (vacc-VSV-NP) the other expressing the glycoprotein of lymphocytic choriomeningitis virus (vacc-LCMV-GP). It was determined whether or not the VSV wt-induced memory T cell response that is protective against vacc-VSV-NP would inhibit growth of the nonrecognized vacc-LCMV-GP.

Tolerance induction by clonal deletion of CD4+8+ thymocytes in vitro does not require dedicated antigen-presenting cells.

The cellular requirements of T cell tolerance induction in the thymus by clonal deletion was investigated by using an in vitro assay: thymocytes from mice expressing a transgenic TcR specific for lymphocytic choriomeningitis virus (LCMV) and H-2Db were co-cultured with various H-2b cell types as antigen-presenting cells in the presence of the antigenic LCMV peptide. The results revealed that all cell lines examined including embryonic and transformed fibroblasts, melanoma cells, cortical thymic epithelial cells, lymphomas and neuronal cells induced an antigen dose-dependent deletion of CD4+8+ thymocytes. Similarly, highly enriched accessory cell populations from thymus and spleen (macrophages, dendritic and cortical epithelial cells, i.

[Model concepts on the development of so-called autoimmune diseases].

The etiology and pathogeneses of autoimmune diseases are only known in a few examples such as myasthenia gravis, some thyroid affections or some forms of pemphigus. This review uses a few experimental models to argue that many autoimmune diseases, particularly those mediated by or dependent upon T cells, may represent immunopathologies triggered by either trivial or unrecognized special infectious agents. In those instances where we know the etiologic agent we call the ensuing disease immunopathological, and in those where we do not know the agent we call it autoimmune.

Enhanced positive selection of a transgenic TCR by a restriction element that does not permit negative selection.

Very little is known about the conformational properties of the MHC molecules that are able to signal positive selection of a given TCR. To try to understand these parameters and to determine whether these requirements are shared with interactions during negative selection and antigen recognition, we have studied selection and antigen recognition of a transgenic TCR (specific for lymphocytic choriomeningitis virus glycoprotein and H-2Db) in the context of two Db mutants, H-2bm13 and H-2bm14. The data showed that the transgenic TCR was not positively selected by the H-2bm14 haplotype but, interestingly, enhanced positive selection was seen in H-2bm13 mice.

Contra: CD8+ T-cell-mediated suppression without 'suppressor' T cells?

This commentary argues that conventional antiviral cytotoxic T cells act suppressively by eliminating antigen-presenting cells, sometimes including lymphocytes, T or B cells expressing relevant antigens of exogenous or endogenous, most commonly of viral origin. They thereby limit expression of antigens, and by eliminating the antigen-expressing cells stop immune responses. However, to argue that induced T cells (or antibodies) function to eliminate or neutralize antigen is the shortest summary of immunology and neither new nor heretic.

Vaccination with two different vaccinia recombinant viruses: long-term inhibition of secondary vaccination.

The effects of immunity to vaccinia virus on the efficiency of vaccination with a vaccinia recombinant virus were studied. In mice the efficiency and duration of the B-cell response to the recombinant gene product of a second vaccinia recombinant virus were suppressed for more than 9 months, i.e.

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.

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.

Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression.

We have examined the expression of the recombination activating gene RAG-1 by in situ hybridization to thymi from mice bearing transgenes for the T-cell receptor (TCR) alpha chain, TCR beta chain, or both TCR alpha and beta chains. RAG-1 transcription was found in the thymic cortex of transgenic mice carrying a single TCR alpha- or TCR beta-chain transgene, comparable to normal mice. However, RAG-1 transcription was strikingly reduced in the thymic cortex from transgenic mice carrying both TCR alpha- and beta-chain genes and expressing major histocompatibility complex (MHC) class I (H-2b) molecules necessary for positive selection of the transgenic TCR.

Thymocytes can tolerize thymocytes by clonal deletion in vitro.

Clonal deletion of thymocytes bearing TCR for self antigens is one major mechanism of T cell tolerance induction. Peptide antigen-induced deletion of thymocytes from alpha beta TCR transgenic mice has been studied using single cell suspension cultures. The results show that antigen-presenting immature CD4+CD8+ thymocytes can tolerize antigen-reactive immature thymocytes in vitro by programmed cell death (apoptosis) 6-8 h after antigen exposure.

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.

Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection.

The TCR-alpha beta of CTL recognize peptide Ag in association with MHC class I molecules. TCR binding should be highly specific to guarantee pathogen specificity and to avoid self-reactivity. Therefore, the in vivo relevance of T cells exhibiting cross-reactivities in vitro and the respective role of the TCR affinities involved are not clear.

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.

Kinetics of clonal deletion varies with tolerizing antigen.

In postnatal AKR/J mice (I-Ek, Mls-1a) potentially autoreactive T-cells bearing V beta 11+ or V beta 6+ TcR are present until day 4, rapidly decreasing thereafter. Clonal deletion of V beta 11+ and V beta 6+ T-cells shows equivalent kinetics and is complete after day 7 to 8. Analysis of transgenic mice expressing a TcR with double specificity for LCMV/H-2Db and for Mls-1a revealed that in mice congenically infected with lymphocytic choriomeningitis virus (LCMV) T-cells bearing the transgenic TcR were already deleted at birth, whereas in uninfected TcR-transgenic Mls-1a mice deletion was delayed.

Immunosuppression by lymphocytic choriomeningitis virus infection: competent effector T and B cells but impaired antigen presentation.

Lymphocytic choriomeningitis virus (LCMV) may cause a severe immunosuppression in mice. Its pathogenesis is apparently dependent on LCMV-specific CD8 effector T cells that mediate the destruction of virus-infected cells which are normally essentially involved in immune responses. Evaluation of various LCMV isolates in this study established a general correlation between their tropism for lymphohemopoietic cells and immunosuppression.

Suppression of virus-specific antibody production by CD8+ class I-restricted antiviral cytotoxic T cells in vivo.

The question of whether virus-induced immunosuppression includes the antibody response against the infecting virus itself was evaluated in a model situation. Transgenic mice expressing the T-cell receptor (TCR) specific for peptide 32-42 of lymphocytic choriomeningitis virus (LCMV) glycoprotein 1 presented by Db reacted with a strong transgenic cytotoxic T-lymphocyte (CTL) response starting on day 3 after infection with a high dose (10(6) PFU intravenously [i.v.

Clonal deletion induced by either radioresistant thymic host cells or lymphohemopoietic donor cells at different stages of class I-restricted T cell ontogeny.

Major histocompatibility complex (MHC) products and self-antigens expressed in the thymus determine the repertoire of mature alpha/beta T cells. While positive selection of self-MHC-restricted T cells is directed by MHC molecules expressed by thymic epithelial cells, negative selection depends to a large extent on self-antigens presented by lymphohemopoietic cells. However, radioresistant components of the thymus also influence negative selection, but it remains controversial whether this is accomplished by clonal deletion, clonal anergy, or other mechanisms.

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.

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.

Positive selection of Tcrb-V10b+ T cells.

The Tcrb-V10b+ T cell population has been examined with a newly established antibody, KT10b, specific for Tcrb-V10b but not Tcrb-V10a. H-2E+ mice have higher levels of Tcrb-V10b+ T cells (4.3%-11.