Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold

Faroudi, Mustapha; Utzny, Clemens; Salio, Mariolina; Cerundolo, Vincenzo; Guiraud, Martine; Müller, Sabina; Valitutti, Salvatore

doi:10.1073/pnas.2334336100

Cited by 193 publications

(220 citation statements)

References 30 publications

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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: 56%

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: 56%

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

2006

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“…20 As PKC not only has an important function in FasL transcription 22,23 but was also reported to localize to the immunological synapse in cytotoxic T lymphocytes after contact with the target cell, 34 we analyzed a possible role of PKC in activation-induced FasL degranulation. Interestingly, TCR-stimulated lytic granule exocytosis was shown to be PKC-dependent.…”

Section: Discussionmentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

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Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4 þ and CD8 þ T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activationinduced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

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“…We have previously shown that individual CTL interacting with cognate target cells exhibit a dual activation threshold reflecting the formation of two distinct immunological synapses (IS) at the CTL͞target cell contact site: the lytic synapse and the stimulatory synapse (3). The term ''lytic synapse'' was used to refer to the polarization of the lytic machinery detectable at both low and high antigen concentrations, and the term ''stimulatory synapse'' was used to refer to the large-scale molecular segregation of surface molecules and signaling components characteristic of a mature IS and occurring only with target cells providing strong antigenic stimuli (3). The formation of a lytic synapse corresponded to full activation of CTL to cytotoxicity (whereas IFN-␥ production was marginal, and calcium mobilization was low and erratic).…”

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confidence: 99%

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

Wiedemann

Depoil²,

Faroudi³

et al. 2006

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

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148

150

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A longstanding paradox in the activation of cytotoxic T lymphocytes (CTL) arises from the observation that CTL recognize and rapidly destroy target cells with exquisite sensitivity despite the fact that cytokine production requires sustained signaling at the immunological synapse. Here we solve this paradox by showing that CTL establish sustained synapses with targets offering strong antigenic stimuli and that these synapses persist after target cell death. Simultaneously, CTL polarize lytic granules toward different cells without discrimination regarding antigenic potential. Our results show that spatiotemporal uncoupling of immunological synapse and lytic granule secretion allows multiple killing and sustained signaling by individual CTL. This unique mechanism of responding to multiple contacts provides remarkable efficiency to CTL function.confocal microscopy ͉ immunological synapse ͉ sustained signaling

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Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold

Cited by 193 publications

References 30 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

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

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

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Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold

Cited by 193 publications

References 30 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

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

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

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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