Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses

Wiedemann, Aurélie; Depoil, David; Faroudi, Mustapha; Valitutti, Salvatore

doi:10.1073/pnas.0600651103

Cited by 147 publications

(175 citation statements)

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“…Cytotoxicity can be induced in CD8 + T cells at low antigen concentrations or after rapid TCR-pMHCI interactions, while cytokine production requires relatively high antigen concentrations and a significantly longer duration of TCR ligation [33][34][35]. Thus, it is not altogether surprising that differences in the kinetics of TCR dissociation between epitope-specific CD8 + T cell populations, as observed in this study, might lead to differences in cytokine profiles.…”

Section: Discussionmentioning

confidence: 57%

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

2006

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Activation of mature CD8 + T cells requires recognition, via the T cell receptor (TCR), of peptide + MHC (pMHC) complexes with an avidity that exceeds a designated threshold. Multiple indicators of T cell avidity have been described that provide unique information on the characteristics of T cell interactions. However, these indicators are routinely used in isolation, and, consequently, little is known about correlations between these measures or which measure, if any, correlates with the quality of the T cell response. Following influenza virus infection of C57BL/6J mice, we analyzed the relative avidities of five epitope-specific CD8 + T cell populations using five different measures. We demonstrated that the quality of CD8 + T cell responses, in terms of cytokine profiles, correlates with TCR dissociation rate and CD8 dependence, but not with the sensitivity to tetramer binding or peptide stimulation. Thus, we propose that, despite significant differences in TCR dissociation rate, the stimulation threshold of influenza-specific CD8 + T cell populations may be equivalent due to compensatory mechanisms largely provided by the CD8 coreceptor. Furthermore, this study shows that different indicators of avidity do not necessarily provide similar information and should be used in combination to obtain an overall picture of the characteristics of TCR binding.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/36390_s.pdf IntroductionThe fate of a T cell depends heavily on the avidity of the TCR:peptide + MHC (pMHC) interaction (reviewed in [1,2]). The collective avidity, or total strength, of the T cell-APC interaction is determined both by the affinity of a single TCR for its pMHC complex and by the number of TCR-pMHC interactions and the contribution of accessory molecules, such as CD4 or CD8, which can also bind MHC molecules upon TCR engagement [3]. In the thymus, immature T cells die if they do not recognize self pMHC molecules with minimal avidity. Conversely, recognition of pMHC exceeding an upper limit of avidity results in negative selection during T cell development. For mature peripheral T cells, upper and lower avidity limits also exist; below a critical threshold T cells do not receive sufficient signal for activation, while studies have shown that too high an avidity also impairs T cell activation, presumably by reducing the ability of the TCR to dissociate from the pMHC complex, thereby impeding serial TCR engagement [4]. Between the upper and lower avidity thresholds, TCR engagement can result in the functional activation of T cells.The term "avidity" is broadly used to describe various distinct features of T cell-APC interactions, including dependence on coreceptors for stimulation, TCR dissociation rate, and thresholds of T cell binding and/or activation. Thus, while correlations have been made between increased T cell "avidity" and functional responsiveness of T cells [5][6][7][8], the definition of avidity is arbitrary and usually based on the meas...

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Section: Discussionmentioning

confidence: 57%

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

2006

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“…For cytotoxic effectors, E, killing an exponentially growing pathogen, one can easily see that effector/ target ratios should play an important role. CTLs cannot kill an infinite number of infected target cells per day because it takes time to locate and bind them, to deliver a lethal hit, and to dissociate to find the next target cell (66,89,97). This "handling time" creates a saturation effect similar to that of Michaelis-Menten enzyme-substrate kinetics (16,26,76).…”

Section: Resultsmentioning

confidence: 99%

“…Asquith et al (6) estimated that CTLs specific for human T-lymphotropic virus type 1 (HTLV-1)-infected cells kill no more than five target cells per day. Stinchcombe et al (89) and Wiedemann et al (97) showed that CTLs kill the target cells that they are associated with in a few minutes. Two-photon microscopy studies suggest that CTL killing takes about half an hour (66).…”

Section: Resultsmentioning

confidence: 99%

“…A1) (6). It takes time to locate and bind them and deliver a lethal hit (66,89,97). This "handling time" creates a saturation effect similar to Michaelis-Menten enzyme-substrate kinetics (16,26,76); i.e., the killing term should take the form ϪkEL/(h ϩ L), where the Michaelis-Menten constant, h, is the pathogen density at which the killing rate per CTL is half-maximal.…”

Section: Appendixmentioning

confidence: 99%

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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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“…On the other hand, the need for stable IS for target-cell killing has been questioned by the observation that low levels of antigen on APCs stimulate Fasmediated CTL killing without formation of stable Kupfer-type IS (19)(20)(21). Thus, the function of stable IS induced by higher antigen levels may be related more closely to perforin-mediated cytotoxicity (20) and/or cytokine secretion (15,22). In addition to these in vitro studies, we and others have described SMACs in T cells in vivo, and the resulting cellular reorganization in "postsynaptic" target cells during the effector phase of an antiviral immune response (14-16, 25, 24) and in human brain tumors (17).…”

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confidence: 99%

Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell function in vivo

Yang

Sanderson

Wawrowsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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To analyze the in vivo structure of antigen-specific immunological synapses during an effective immune response, we established brain tumors expressing the surrogate tumor antigen ovalbumin and labeled antigen-specific anti-glioma T cells using specific tetramers. Using these techniques, we determined that a significant number of antigen-specific T cells were localized to the brain tumor and surrounding brain tissue and a large percentage could be induced to express IFNγ when exposed to the specific ovalbuminderived peptide epitope SIINFEKL. Detailed morphological analysis of T cells immunoreactive for tetramers in direct physical contact with tumor cells expressing ovalbumin indicated that the interface between T cells and target tumor cells displayed various morphologies, including Kupfer-type immunological synapses. Quantitative analysis of adjacent confocal optical sections was performed to determine if the higher frequency of antigen-specific antiglioma T cells present in animals that developed an effective antitumor immune response could be correlated with a specific immunological synaptic morphology. Detailed in vivo quantitative analysis failed to detect an increased proportion of immunological synapses displaying the characteristic Kupfer-type morphology in animals mounting a strong and effective antitumor immune response as compared with those experiencing a clinically ineffective response. We conclude that an effective cytolytic immune response is not dependent on an increased frequency of Kupfer-type immunological synapses between T cells and tumor cells.anti-tumor immunity | brain tumors | immunotherapy

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Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses

Cited by 147 publications

References 29 publications

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

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

Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell function in vivo

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Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses

Cited by 147 publications

References 29 publications

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8+ T cell responses

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8+ T cell responses

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

Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell function in vivo

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A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8⁺ T cell responses

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