CD8 T cell competition for dendritic cells<i>in vivo</i>is an early event in activation

Willis, Richard A.; Kappler, John W.; Marrack, Philippa

doi:10.1073/pnas.0605130103

Cited by 78 publications

(83 citation statements)

References 44 publications

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“…T-cell expansion during the virus challenge possibly due to CTL competition [29][30][31]. As we observed cross-priming of GP33 and NP396 with i-HEK-LyUV cells, one would expect to see a response dominated by GP33 and NP396 during a subsequent virus challenge.…”

Section: Discussionmentioning

confidence: 78%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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Section: Discussionmentioning

confidence: 78%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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“…The model presented above (see THEORY) studies replication rates observed in SIV-infected monkeys; i.e., the maximum replication rate of the virus is 1.5 day Ϫ1 , which is considerably faster than the growth rate of the immune response of approximately 1 day Ϫ1 (21,22). The model includes naive (or memory) CD8 ϩ T cells that are activated at a sufficiently high antigen density, which is weighted by intraclonal competition (24,40,50,51,52,98) to account for the late recruitment of large memory populations (22). During the first few weeks of acute infection, there are many target cells in the gut mucosa, and viral growth is exponential at the predefined rate of 1.5 day Ϫ1 (see Appendix).…”

Section: Resultsmentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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Although CD8 ؉ T cells play an important role in controlling viral infections, boosting specific CD8 ؉ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8 ؉ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8 ؉ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8 ؉ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid-or protein-based vaccines.

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“…This method is especially important to allow tracking of early differentiation events of naive T cells, which are too few in number to be followed in a nonmanipulated immune system. The high frequency of T cells with a single specificity is rather unphysiologic, and recent studies clearly show that the frequency of antigen-specific precursor cells has a strong influence on their subsequent proliferation, differentiation and memory formation [26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Identification and isolation of murine antigen‐reactive T cells according to CD154 expression

et al. 2007

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T helper (Th) cells are central regulators of adaptive immune responses. However, the detection of the small number of Th cells specific for a particular antigen or pathogen is still a major challenge. CD154 was recently introduced as a marker for antigen-specific Th cells. To date, this technology was not applicable for mice -arguably the most important immunological model system. CD154 is difficult to detect due to its rapid removal from the cell surface upon binding to CD40 during antigen-specific activation by APC. We present an efficient strategy to block the degradation of murine CD154 by combined use of antibodies against CD40 and CD154. This strategy makes CD154 easily accessible for surface staining, which allows isolation and expansion of rare antigen specific T cells. Importantly, CD154 identified all specific T cells in strongly Th1-or Th2-polarized immune responses against pathogens like Salmonella typhimurium and Heligmosomoides polygyrus, independent of their potential to produce cytokines. We demonstrate that CD154 can in fact be used as a reliable marker for antigen-specific CD4 T cells in mice, offering a unique option to analyze, isolate and rapidly expand the entire pool of Th-cells generated during a physiological T cell response in vivo.

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CD8 T cell competition for dendritic cellsin vivois an early event in activation

Cited by 78 publications

References 44 publications

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Identification and isolation of murine antigen‐reactive T cells according to CD154 expression

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CD8 T cell competition for dendritic cellsin vivois an early event in activation

Cited by 78 publications

References 44 publications

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Identification and isolation of murine antigen‐reactive T cells according to CD154 expression

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Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus