Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses (original) (raw)
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Immunization with vaccinia virus resulted in long-lasting protection against smallpox and was the approach used to eliminate natural smallpox infections worldwide. Due to the concern about the potential use of smallpox virus as a bioweapon, smallpox vaccination is currently being reintroduced. Severe complications from vaccination were associated with congenital or acquired T cell deficiencies, but not with congenital agammaglobulinemia, suggesting the importance of T cell immunity in recovery from infection. In this report, we identified two CD8 ϩ T cell epitopes restricted by the most common human major histocompatibility complex (MHC) class I allele, HLA-A * 0201. Both epitopes are highly conserved in vaccinia and variola viruses. The frequency of vaccinia-specific CD8 ϩ T cell responses to these epitopes measured by interferon (IFN)-␥ enzyme-linked immunospot (ELISPOT) assay and HLA/peptide tetramer staining peaked 2 wk after primary immunization and then declined, but were still detectable 1 to 3 yr after primary immunization. 2 wk after immunization, IFN-␥ -producing cells specific to these two epitopes were 14% of total vaccinia virus-specific IFN-␥ -producing cells in one donor, 35% in the second donor, and 6% in the third donor. This information will be useful for studies of human T cell memory and for the design and analyses of the immunogenicity of experimental vaccinia vaccines.
PLoS Pathogens, 2012
Vaccination is highly effective in preventing various infectious diseases, whereas the constant threat of new emerging pathogens necessitates the development of innovative vaccination principles that also confer rapid protection in a case of emergency. Although increasing evidence points to T cell immunity playing a critical role in vaccination against viral diseases, vaccine efficacy is mostly associated with the induction of antibody responses. Here we analyze the immunological mechanism(s) of rapidly protective vaccinia virus immunization using mousepox as surrogate model for human smallpox. We found that fast protection against lethal systemic poxvirus disease solely depended on CD4 and CD8 T cell responses induced by vaccination with highly attenuated modified vaccinia virus Ankara (MVA) or conventional vaccinia virus. Of note, CD4 T cells were critically required to allow for MVA induced CD8 T cell expansion and perforin-mediated cytotoxicity was a key mechanism of MVA induced protection. In contrast, selected components of the innate immune system and B cellmediated responses were fully dispensable for prevention of fatal disease by immunization given two days before challenge. In conclusion, our data clearly demonstrate that perforin-dependent CD8 T cell immunity plays a key role in MVA conferred short term protection against lethal mousepox. Rapid induction of T cell immunity might serve as a new paradigm for treatments that need to fit into a scenario of protective emergency vaccination.
The Journal of Immunology, 2005
Primary immunization of healthy adults with vaccinia virus induces a local vesicle or "take" in the majority of vaccinees that previously has been shown to correlate with protection against smallpox. However, the immunologic mechanisms underlying this protective response in humans are not well characterized. We have studied human CD8 ؉ T cells for the expression patterns of phenotypic markers and cytolytic effector molecules before and after primary smallpox immunization using nine-color polychromatic flow cytometry. One month after immunization, vaccinees developed vaccinia virus-specific CD8 ؉ T cells with an effector cell phenotype containing both granzyme A and granzyme B. One year after immunization, we found a significant decrease in granzyme B containing cells and an increased memory cell phenotype in virus-specific CD8 ؉ T cells. Perforin was rarely expressed directly ex vivo, but was highly expressed after Ag-specific activation in vitro. Together, these data suggest an important role for effector CD8 ؉ T cells in controlling poxvirus infection, and have implications for our understanding of human CD8 ؉ T cell differentiation.
The Journal of Infectious Diseases, 2002
This study measured the ability of a standard smallpox vaccine, given by scarification (by bifurcated needle), to induce primary human vaccinia virus-specific cytotoxic and interferon (IFN)-gproducing T lymphocyte responses. Because protection against smallpox may be mediated in part by T cell memory responses induced by vaccination, an analysis of the induction of primary human cytotoxic T lymphocytes (CTL) and IFN-g-producing T cell responses was performed. Although smallpox is no longer an epidemic threat under natural conditions, vaccination is still recommended for persons working with vaccinia viruses in the laboratory and for those who may be at risk from the potential use of smallpox virus as a bioterrorism agent. The results demonstrate that smallpox vaccine given by bifurcated needle induces strong vaccinia virus-specific CD8 + CTL and IFN-g-producing T cell responses and provide baseline information useful for planning the immunologic assessment of future smallpox vaccines.
Cellular and Humoral Immunity against Vaccinia Virus Infection of Mice
The Journal of Immunology, 2004
Despite the widespread use of vaccinia virus (VV) as a vector for other Ags and as the smallpox vaccine, there is little information available about the protective components of the immune response following VV infection. In this study, protection against wild-type VV was evaluated in mice with respect to the relative contributions of CD8 ؉ T cells vs that of CD4 ؉ T cells and Ab. C57BL/6 mice primed with the Western Reserve strain of VV mount significant IgM and IgG Ab responses, specific cytotoxic T cell responses, IFN-␥ responses in CD4 ؉ and CD8 ؉ T cells, and effectively clear the virus. This protection was abrogated by in vivo depletion of CD4 ؉ T cells or B cells in IgH ؊/؊ mice, but was not sensitive to CD8 ؉ T cell depletion alone. However, a role for CD8 ؉ T cells in primary protection was demonstrated in MHC class II ؊/؊ mice, where depleting CD8 ؉ T cells lead to increase severity of disease. Unlike control MHC class II ؊/؊ mice, the group depleted of CD8 ؉ T cells developed skin lesions on the tail and feet and had adrenal necrosis. Adoptive transfer experiments also show CD8 ؉ T cells can mediate protective memory. These results collectively show that both CD4 ؉ and CD8 ؉ T cell-mediated immunity can contribute to protection against VV infection. However, CD4 ؉ T cell-dependent anti-virus Ab production plays a more important role in clearing virus following acute infection, while in the absence of Ab, CD8 ؉ T cells can contribute to protection against disease.
Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines
Immunity, 2008
To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8 + T cells responding to the live yellow fever virus and smallpox vaccines-two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8 + T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8 + T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8 + T cells specific for persistent viruses. These results provide a benchmark for CD8 + T cell responses induced by two of the most effective vaccines ever developed.
Long term recall of memory CD8 T cells in mice to first and third generation smallpox vaccines
Vaccine, 2011
Since long-term immunity is a critical component of any effective vaccine, we compared over a 15 month period, the strength, durability and specificity of immunity of an attenuated smallpox vaccine Modified Vaccinia Ankara (MVA) to the New York City Board of Health (NYCBH) vaccine. The frequencies of CD8 + T cells to an immunodominant CD8 T cell epitope B8R 20-27 remained remarkably stable in mice given either MVA or NYCBH. Both groups were also protected from a lethal intranasal challenge with Western Reserve strain of vaccinia virus (VACV-WR). Cytokine responses to virus-specific peptides were detectable with significant boosting upon challenge. Expression of most phenotypic markers that define antigen-specific memory CD8 T cells was similar while CD27 was differentially expressed on lung-specific T cells compared to the spleen. Our data indicate robust vaccinia-specific CD8 + T cell recall responses to lethal secondary challenge in protected mice with no apparent effect of age on T cell pools established much earlier in life.
Human Immunology, 2008
Immunization with vaccinia virus (VACV) resulted in long-lasting protection against smallpox and successful global eradication of the disease. VACV elicits strong cellular as well as humoral immune responses. Although neutralizing antibody is essential for protection, cellular immunity seems to be more important for recovery from infection in humans. We analyzed the immunodominance hierarchy of 73 previously identified VACV human CD8 + T cell epitopes restricted by HLA-A1, A2, A3, A24, B7 or B44 alleles or the alleles belonging to one of these supertypes in 56 donors after primary VACV immunization. Except for the responses to HLA-A24 supertype-restricted epitopes, there were no consistent patterns of epitope immunodominance among donors sharing the same HLA alleles or supertypes, which is in sharp contrast with the mouse studies. We, however, identified 12 epitopes that were recognized by ≥20% of donors sharing the same HLA allele; six of these contributed ≥20% of the total VACV-specific T cell response in at least one individual. VACVspecific CD8 + T cell responses targeted a group of epitopes, "relatively dominant" epitopes, without a strong immunodominance hierarchy in humans, which may be advantageous to humans to prevent the emergence of T cell escape mutants.