Memory CD8<sup>+</sup>T Cells Specific for a Single Immunodominant or Subdominant Determinant Induced by Peptide-Dendritic Cell Immunization Protect from an Acute Lethal Viral Disease

Remakus, Sanda; Rubio, Daniel; Ma, Xueying; Sette, Alessandro; Sigal, Luis J.

doi:10.1128/jvi.00981-12

Cited by 30 publications

(30 citation statements)

References 56 publications

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“…This suggests that the generation, maintenance, and recall response of CD8 M to nonattenuated VACV may be less dependent on T H than strains with poorer replicative potential. Another reason for the differences might be that, similar to SalekArdakani et al (25), we determined polyclonal responses against a natural epitope shared by VACV and ECTV (31,36) rather than TCR transgenic responses to ectopic determinants (14, 21-23, 37, 38). In addition to attenuation, other factors that may affect the need for T H and protective capacity are the dose of VACV and the route of inoculation (20,25).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that CD8 M induced by VACV immunization become CD8 E and protect mice from mousepox, strongly suggesting that the establishment of a pool of CD8 M cells is one of the mechanisms whereby the smallpox vaccine protects from pathogenic OPVs (10,11,36). Given the importance of CD8 M induced by VACV in protection from lethal OPVs, we thought that it was important to determine the impact of T H in the establishment of this form of protective immunity.…”

Section: Discussionmentioning

confidence: 99%

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CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

Fang

Remakus

Roscoe

et al. 2015

J Virol

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It has been shown in various infection models that CD4؉ T cell help (T H ) is necessary for the conditioning, maintenance, and/or recall responses of memory CD8 ؉ T cells (CD8 M) . Yet, in the case of vaccinia virus (VACV), which constitutes the vaccine used to eradicate smallpox and is a candidate vector for other infectious diseases, the issue is controversial because different groups have shown either T H dependence or independence of CD8 M conditioning, maintenance, and/or recall response. In agreement with some of these groups, we show that T H plays a role in, but is not essential for, the maintenance, proliferation, and effector differentiation of polyclonal memory CD8 ؉ T cells after infection with wild-type VACV strain Western Reserve. More important, we show that unhelped and helped anti-VACV memory CD8 ؉ T cells are similarly efficient at protecting susceptible mice from lethal mousepox, the mouse equivalent of human smallpox. Thus, T H is not essential for the conditioning and maintenance of memory CD8؉ T cells capable of mounting a recall response strong enough to protect from a lethal natural pathogen. Our results may partly explain why the VACV vaccine is so effective. IMPORTANCE We used vaccinia virus (VACV)-a gold standard vaccine-as the immunogen and ectromelia virus (ECTV) as the pathogen to demonstrate that the conditioning and maintenance of anti-VACV memory CD8 ؉ T cells and their ability to protect against an orthopoxvirus (OPV) infection in its natural host can develop in the absence of CD4؉ T cell help. Our results provide important insight to our basic knowledge of the immune system. Further, because VACV is used as a vaccine in humans, our results may help us understand how this vaccine induces protective immunity in this species. In addition, this work may partly explain why VACV is so effective as a vaccine. F ollowing primary viral infection or vaccination, naive antiviral CD8ϩ T cells (CD8 N ) contribute to virus control by expanding and becoming effectors (CD8 E ) that kill infected cells and produce antiviral cytokines such as gamma interferon (IFN-␥) (1). If the virus is eliminated, most CD8 E die but many survive to become resting memory CD8 ϩ T cells (CD8 M ) that remain at higher frequencies than the original CD8 N population (2). If a secondary infection occurs, the CD8 M rapidly expand and become secondary CD8 E . CD8 M can contribute to reduce the severity of a secondary viral infection by achieving high numbers of effectors more rapidly than CD8 N would. Moreover, the efficient generation of CD8 M may be important for the effectiveness of some vaccines.The genus Orthopoxvirus (OPV) comprises highly conserved DNA viruses that are antigenically highly cross-reactive. Vaccinia virus (VACV) is an OPV that can infect multiple species but is poorly pathogenic and highly immunogenic. Because of this, it was exploited as the vaccine that eliminated human smallpox, a highly lethal disease caused by the human-specific OPV variola virus (VARV). Thus, VACV remains as the gol...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

Fang

Remakus

Roscoe

et al. 2015

J Virol

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“…We limited the analysis to peptides that contain 9-11 residues, because the large majority conforms to this length while a small fraction contains longer peptides. the protective potential of individual antigenic determinants, which were mostly focused on a few rapidly detectable specificities (31)(32)(33)(34). Therefore, the actual array of critical antigenic determinants driving protective TCD8 responses during a natural infection or after vaccination remains unknown.…”

Section: Resultsmentioning

confidence: 99%

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Gilchuk¹,

Spencer²,

Conant³

et al. 2013

J. Clin. Invest.

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141

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CD8 + T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection -information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.

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“…CD8 + T cells specific to epitopes encoded by pathogens are generally organized into hierarchies based on the magnitude of the response (immunodominance). The most immunodominant epitopes are not necessarily the most protective [20][21][22][23], and perturbations of the epitope hierarchy may lead to different immune response outcomes [22]. The relationship between CD8 + T cell hierarchy and cross-reactivity could be significant in DENV pathogenesis and protection.…”

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confidence: 99%

“…CD8 + T cells specific to epitopes encoded by pathogens are generally organized into hierarchies based on the magnitude of the response (immunodominance). The most immunodominant epitopes are not necessarily the most protective [20][21][22][23], and perturbations of the epitope bs_bs_banner Clinical and Experimental Immunology ORIGINAL ARTICLE …”

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Dengue virus-infected human dendritic cells reveal hierarchies of naturally expressed novel NS3 CD8 T cell epitopes

Piazza

Campbell

Marques

et al. 2014

Clinical and Experimental Immunology

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SummaryDetailed knowledge of dengue virus (DENV) cell-mediated immunity is limited. In this study we characterize CD8 + T lymphocytes recognizing three novel and two known non-structural protein 3 peptide epitopes in DENVinfected dendritic cells. Three epitopes displayed high conservation (75-100%), compared to the others (0-50%). A hierarchy ranking based on magnitude and polyfunctionality of the antigen-specific response showed that dominant epitopes were both highly conserved and cross-reactive against multiple DENV serotypes. These results are relevant to DENV pathogenesis and vaccine design. Dengue virus (DENV) is a major global health threat [1] and the cause of severe haemorrhagic fever (DHF), a lifethreatening disease when not addressed correctly [2]. DENV exists as four distinct serological types and DHF occurs at increased frequency after exposure to different (heterotypic) DENV serological types from the one that was first encountered [3,4]. Cross-reactive, CD8 Keywords+ cytotoxic T lymphocytes (CTL), together with other factors, are important in the aetiology of DHF, but their role is still unclear [5][6][7][8][9][10]. Disappointing results from a dengue vaccine in a recent paediatric clinical trial [11] also suggest that, in addition to high titre neutralizing antibodies specific for structural proteins, CTL directed to nonstructural viral proteins are likely to be important correlates of protection.T cell responses to the four DENV serotypes are quantitatively and qualitatively different [7,[12][13][14][15]. DENV crossreactive, memory CTL have reduced killing activity and are more prone to apoptosis upon encounter with novel DENV epitope variants encoded by the heterotypic serotype [16,17], although recent evidence has challenged this model [10]. Also, virus variants that result in diminished or abolished binding of DENV CTL epitopes to major histocompatibility complex (MHC)-I could result in the higher degree of mortality within epidemics [18].Two recent detailed analyses [10,19] have considerably expanded the existing knowledge [8] of DENV-specific T cell epitopes. There is still, however, a relative paucity of information regarding which DENV CTL epitopes correlate with protection or disease. DENV is translated as a single polyprotein that is subsequently processed into 10 mature, non-structural and structural proteins each containing CTL epitopes [8]. However, non-structural protein 3 (NS3) contains more epitopes (31% of the total) compared to the other nine DENV proteins and is also the most immunogenic, followed by NS5 (22% of the total) [7,8,10,19].Characterization of DENV CTL epitopes has so far relied almost exclusively on the use of synthetic peptides with sequences obtained from MHC-I binding prediction algorithms [10] or from testing pools of longer, overlapping peptides organized in matrices which are then deconvoluted. Even more importantly, few, if any, studies have confirmed the expression of these epitopes in DENVinfected cells and/or have determined the optimal length of the CTL e...

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Memory CD8⁺T Cells Specific for a Single Immunodominant or Subdominant Determinant Induced by Peptide-Dendritic Cell Immunization Protect from an Acute Lethal Viral Disease

Cited by 30 publications

References 56 publications

CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Dengue virus-infected human dendritic cells reveal hierarchies of naturally expressed novel NS3 CD8 T cell epitopes

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Memory CD8+T Cells Specific for a Single Immunodominant or Subdominant Determinant Induced by Peptide-Dendritic Cell Immunization Protect from an Acute Lethal Viral Disease

Cited by 30 publications

References 56 publications

CD4+T Cell Help Is Dispensable for Protective CD8+T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

CD4+T Cell Help Is Dispensable for Protective CD8+T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Dengue virus-infected human dendritic cells reveal hierarchies of naturally expressed novel NS3 CD8 T cell epitopes

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Memory CD8⁺T Cells Specific for a Single Immunodominant or Subdominant Determinant Induced by Peptide-Dendritic Cell Immunization Protect from an Acute Lethal Viral Disease

CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization