Vaccine route, dose and type of delivery vector determine patterns of primary CD8 + T cell responses

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T cell receptor-transgenic F5 mice were used to assess primary CD8 + T cell responses to a modified virus Ankara (MVA)-vectored vaccine in the absence of CD4 + T cell help. Naive, CD8-enriched, CFSE-labelled F5 cells were transferred into normal or CD4 + celldepleted mice and the mice were vaccinated with MVA.HIVA-NP. At different time points during the primary response, F5 cells were re-isolated and analysed on divisional basis for a number of parameters. We demonstrated that the primary CD8 + T cell response in the absence of CD4 + T cell help differed from that in normal CD4 + cellundepleted mice. While in the absence of CD4 + T cell help, the initial migratory progress from the local response to a systemic one was not grossly affected, the proportion of dying F5 cells during the expansion phase was markedly increased and resulted in an overall smaller expansion and significantly decreased frequency of CD8 + T cell memory after contraction. T cells primed without help displayed accelerated proliferation and activation, while expression of interferon-c remained similar. These phenomena were observed in the lymph nodes draining the MVA.HIVA-NP immunization site and were similar, but delayed by 2-3 days in spleen and non-draining lymph nodes. IntroductionCD8 + T cells form an important part of the immune defence against many intracellular pathogens including viruses. Historically, CD8 + T cell responses against viral infections were considered to be independent from 'help' provided by CD4 + T cells. This was explained by direct activation of antigen-presenting DC by viruses, which provided ligands for Toll-like receptors and proinflammatory signals [1][2][3]. Recently, this view was revised by studies of non-inflammatory antigens which suggested that while primary CD8 + T cell response was CD4 + T cell-independent, secondary CD8 + T cell response, i.e. development of functional memory, was dependent on CD4 + T cell help during priming. These data led to the formulation of a programming model [4][5][6]. In contrast, another set of recent studies pointed towards an environmental model and proposed that CD4 + T cells were required to enhance survival of fully functional memory CD8 + T cells rather than imparting essential programming during the primary response [7,8]. The differences in these conclusions may be explained by the use of different antigens and immunization protocols, which might lead to differential activation of DC. Collectively, these and other experiments [9][10][11][12][13] not required for triggering the CD8 + T cell program of multiple cell divisions, effector function maturation and cell number contraction, but was needed for differentiation into functional CD8 + T cell memory and/or its maintenance.To date, most studies investigated secondary responses to make conclusions about the dependence of the CD8 + T cell responses on CD4 help. This is partially because induction of a good memory is the ultimate aim of a successful vaccination, but also because primary CD8 + T cell responses to non-inf...

Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 94%

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confidence: 88%

Section: Construction Of the Mvahiva-np Vaccinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help

Estcourt¹,

McMichael²,

Hanke³

2005

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Understanding what makes a good versus a bad vaccine

Harari

Pantaleo

2005

The majority of the HIV vaccines under development are aimed at stimulating T cell responses. Therefore, it is critical to delineate the factors regulating the generation of the T cell responses and to develop strategies maximizing vaccine-induced T cell responses. The identification of these factors and the delineation of the kinetics of the generation of vaccine-induced immune responses have been hard to investigate, due to the limited number of precursor naive antigen-specific T cells. To overcome these obstacles, Estcourt and collaborators have developed an elegant strategy that consists of an in vivo mouse model employing transfer of naive CFSE-labeled TCR-transgenic T lymphocytes into syngeneic nontransgenic recipients prior to vaccination. Using this model, the authors demonstrate that the dose, the route of administration and the type of vaccine determine the magnitude, the dissemination and the kinetics of vaccineinduced T cell responses. Furthermore, the mouse model of Estcourt and collaborators may represent the basis for the development of powerful in vivo experimental strategies to evaluate vaccine candidates.

Combined single‐clade candidate HIV‐1 vaccines induce T cell responses limited by multiple forms of in vivo immune interference

Larke

Wagner

et al. 2007

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We assessed in mice whether broad CD8 + T cell responses capable of efficient recognition of multiple HIV-1 clades could be induced using current single-clade vaccine constructs that were or will be used in clinical trials in Europe and Africa. We found that single-clade A, B and C vaccines applied alone induced only limited crossclade reactivity and that the epitope hierarchy varied according to the immunizing clade. However, combining single-clade HIV-1 vaccines into multi-clade formulations resulted in multiple forms of in vivo immune interference such as original antigenic sin and antagonism, which dampened or even abrogated induction of responses to epitope variants and reduced the breadth of induced T cell responses. Simultaneous administration of individual clade-specific vaccines into anatomically separated sites on the body alleviated antagonism and increased the number of detectable epitope responses. Although cross-reactivity of murine CD8 + T cells does not directly translate to humans, the molecular interactions involved in triggering T cell responses are the same in mouse and man. Thus, these results have important ramifications for the design of both prophylactic and therapeutic vaccines against HIV-1 and other highly variable pathogens.