Responses against a Subdominant CD8(+) T Cell Epitope Protect against Immunopathology Caused by a Dominant Epitope

Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(8):4673-80. DOI: 10.4049/jimmunol.1001606
Source: PubMed


CD8(+) T cell responses are critical for the control of virus infections. Following infection, epitope-specific responses establish an unpredictable but reproducible pattern of dominance that is dictated by a large number of both positive and negative factors. Immunodomination, or diminution of subdominant epitope-specific responses by dominant epitopes, can play a substantial role in the establishment of epitope hierarchy. To determine the role of a dominant (K(d)M2(82-90)) and a subdominant (D(b)M(187-195)) epitope of respiratory syncytial virus in viral control and immunodomination, MHC-binding anchor residues in the two epitopes were mutated individually in recombinant infectious viruses, greatly reducing or deleting the epitope-specific CD8(+) T cell responses. Neither mutation negatively affected viral clearance in mice, and compensation by the unmutated epitope was seen in both cases, whereas compensation by five other subdominant epitopes was minimal. Mutation of the dominant K(d)M2(82-90) response resulted in effective viral clearance by the subdominant epitope with less illness, whereas mutation of the subdominant D(b)M(187-195) response resulted in overcompensation of the already dominant K(d)M2(82-90) epitope, and increased severity of illness. Increased illness was associated with poor functionality of the abundant population of CD8(+) T cells specific to the dominant K(d)M2(82-90) epitope, as measured by the percentage and magnitude of IFN-γ production. These data demonstrate efficient viral clearance, and a protective effect of subdominant CD8(+) T cell responses.

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    • "Cells specific for this epitope also often lack functionality with regard to cytokine production and cytotoxicity in vivo [18], [19]. The cytotoxic activity of the subdominant DbM187–195-specific T cell response is higher than that of KdM282–90-specific response, resulting in better viral clearance and less illness in mice with a dampened KdM282–90-specific response [18]. "
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    ABSTRACT: Our previous work has characterized the functional and clonotypic features of two respiratory syncytial virus (RSV) epitope-specific T cell responses in mice. Following single-cell sequencing, we selected T cell receptor sequences to represent both a public and a private clone specific for the dominant KdM282-90 epitope for the generation of T cell receptor transgenic (TCR Tg) mice. We evaluated cells from these TCR Tg strains for three major functions of CD8+ T cells: proliferation, cytokine production and cytolytic activity. In vitro comparisons of the functional characteristics of T cells from the newly-generated mice demonstrated many similarities in their responsiveness to cognate antigen stimulation. Cells from both TRBV13-1 (private) and TRBV13-2 (public) TCR Tg mice had similar affinity, and proliferated similarly in vitro in response to cognate antigen stimulation. When transferred to BALB/c mice, cells from both strains demonstrated extensive proliferation in mediastinal lymph nodes following RSV infection, with TRBV13-2 demonstrating better in vivo proliferation. Both strains similarly expressed cytokines and chemokines following stimulation, and had similar Granzyme B and perforin expression, however cells expressing TRBV13-1 demonstrated better cytolytic activity than TRBV13-2 cells. These new, well-characterized mouse strains provide new opportunities to study molecular mechanisms that control the phenotype and function of CD8+ T cell responses.
    PLoS ONE 06/2014; 9(6):e99249. DOI:10.1371/journal.pone.0099249 · 3.23 Impact Factor
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    • "Further advantages of epitope-based vaccines over current vaccines include increased potency and other qualitative aspects of the immune response, particularly when compared to the use of whole antigens. Epitope-based immunization has been shown to be effective in eliciting responses against multiple B cell, CD4+ T cell or CD8+ T cell epitopes, including subdominant CD8+ T cell epitopes [5]–[13]. Most importantly, the epitope approach has been used successfully to treat and/or prevent different types of disease in animal models, including acute or chronic viral infections [6], [7], [14], [15], parasitic and microbial infections [16], and cancer [17]. "
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    ABSTRACT: Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP) vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+) and/or CD8(+) T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8(+) T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+) T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.
    PLoS ONE 08/2012; 7(8):e40928. DOI:10.1371/journal.pone.0040928 · 3.23 Impact Factor
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    • "This approach is likely to identify immunogenic and protective proteins from the normally subdominant pool of proteins. This outcome will likely be the case given the evidence from other models of intracellular infection that vaccination against subdominant epitopes can produce effective cellular immune responses (Riedl et al., 2009; Ruckwardt et al., 2010; Im et al., 2011). An additional consideration that would support our approach is that, from the perspective of the T cell response, cross-reactivity is also favored by the T cells themselves since the T cell receptor is multispecific due to structural flexibility and interactions with only a few residues within the presented peptides. "
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    ABSTRACT: Scrub typhus is a severe mite-borne infection caused by Orientia tsutsugamushi, an obligately intracellular bacterium closely related to Rickettsia. The disease explains a substantial proportion of acute undifferentiated febrile cases that require hospitalization in rural areas of Asia, the North of Australia, and many islands of the Pacific Ocean. Delayed antibiotic treatment is common due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation. The systemic infection of endothelial cells that line the vasculature with Orientia can lead to many complications and fatalities. In survivors, immunity does not last long, and is poorly cross-reactive among numerous strains. In addition, chronic infections are established in an unknown number of patients. All those characteristics justify the pursuit of a prophylactic vaccine against O. tsutsugamushi; however, despite continuous efforts to develop such a vaccine since World War II, the objective has not been attained. In this review, we discuss the history of vaccine development against Orientia to provide a clear picture of the challenges that we continue to face from the perspective of animal models and the immunological challenges posed by an intracellular bacterium that normally triggers a short-lived immune response. We finish with a proposal for development of an effective and safe vaccine for scrub typhus through a new approach with a strong focus on T cell-mediated immunity, empirical testing of the immunogenicity of proteins encoded by conserved genes, and assessment of protection in relevant animal models that truly mimic human scrub typhus.
    Frontiers in Cellular and Infection Microbiology 01/2012; 2:170. DOI:10.3389/fcimb.2012.00170 · 3.72 Impact Factor
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