Altered Peptide Ligands Induce Delayed CD8-T Cell Receptor Interaction—a Role for CD8 in Distinguishing Antigen Quality

Yachi, Pia P.; Ampudia, Jeanette; Żal, Tomasz; Gascoigne, Nicholas R. J.

doi:10.1016/j.immuni.2006.05.015

Cited by 94 publications

(130 citation statements)

References 34 publications

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“…Note that in ref. 27 only the number of activated T cells was measured, but not actual phosphorylation levels, which turned out to be very sensitive to coreceptor-MHC interactions in later experiments from the same laboratory(28) (although still being above the activation threshold). These observations suggested that CD8 contributes to T-cell activation via an unknown mechanism unrelated to surface stabilization of pMHC (29).…”

Section: Discussionmentioning

confidence: 99%

“…The simulated surface is divided into square chambers of the length L = 100 Å (0.01 μm), which implies that we simulate 100 × 100 chambers. The dimensions of the individual chamber are chosen to correspond to the range of attractive interactions between membrane-bound proteins (27). We ignore internal degrees of freedom in proteins, and proteins can react with each other provided that both are in the same chamber (i.e., they are within the range of interactions).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Artyomov

Lis

Devadas

et al. 2010

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

171

144

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The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptidemajor histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR-pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr-pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function.M embrane proteins CD4 and CD8 are expressed on T helper cells and cytotoxic T lymphocytes, respectively, that are known to augment the sensitivity and response of T cells to cognate peptide-major histocompatibility (pMHC) ligands (1-3). It is generally thought that the ability of these coreceptors to enhance T-cell responses is due to two main effects: (i) Binding of CD4 and CD8 to MHC class II and class I molecules helps stabilize weak T-cell receptor (TCR)-pMHC interactions; and (ii) the Src kinase, Lck, which is bound to the cytoplasmic tail of coreceptors, is efficiently recruited to the TCR complex upon coreceptor binding to the MHC, thereby enhancing the initiation of TCR signaling (3, 4).Surface plasmon resonance (SPR) analyses show that the halflives characterizing coreceptor-MHC interactions are <35 ms (off rate >20 s −1 , the resolution of SPR instruments) for both CD4 and CD8 (5-7). It is difficult to understand how the two effects noted above can be potentiated by such fleeting interactions. For example, consider the effect of coreceptor-MHC interactions in stabilizing the TCR-pMHC complex. A typical agonist pMHC ligand is bound to a TCR for ≈10,000 ms (corresponding to an off rate of 0.1 s −1 ) (8). Thus, during the lifetime of the TCR-pMHC bond a coreceptor would disengage from the MHC ≈1,000 times, making it implausible that stabilization of TCR-pMHC interactions would be achieved. Recent data measuring TCR binding within a synapse (9) show that it is less stable, perhaps 1,000 ms for an average TCR-ligand interaction due to actin polymerization activity, but this is still far in excess of what has been reported for CD4 and CD8 interactions.However, CD8 has been found to stabilize pMHC binding to CD8+ T-cell surfaces (10, 11) and augment sensitivity (2, 12). In contrast, past studies (13,14) and recent in situ measurements at intercellular junctions show that CD4 does not stabilize the interactions of TCR with class II pMHC molecules (9). However, CD4 does enhance the sensitivity of T helper cells (1,9,15,16). As the binding affinity of CD4 for the MHC ectodomain has been reported to be ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Artyomov

Lis

Devadas

et al. 2010

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

171

144

View full text Add to dashboard Cite

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“…Because the polarized release reported by the Janeway group was only observed at low levels of TCR stimulation, we investigated the possibility that the absence of synaptic restriction in our live-cell imaging paradigm was due to strong signaling at the OT-I TCR. To control the level of antigenic stimulation, we pulsed astrocytes with increasing concentrations of the canonical OT-I epitope SIINFEKL and two altered peptide ligands, SIIG-FEKL and EIINFEKL, which have been demonstrated to mediate respectively intermediate and low signaling at the OT-I TCR (15). After washing, cocultures of astrocytes and OT-I T cells were incubated for 6 h, fixed, and immunolabeled for IFN-γ, LFA-1 and phosphorylated Stat1.…”

Section: T-cell Signaling To Nontarget Cells Is Independent Of Antigementioning

confidence: 99%

Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells

Sanderson

Puntel

Kroeger

et al. 2012

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

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Following antigen recognition on target cells, effector T cells establish immunological synapses and secrete cytokines. It is thought that T cells secrete cytokines in one of two modes: either synaptically (i.e., toward antigenic target cells) or multidirectionally, affecting a wider population of cells. This paradigm predicts that synaptically secreted cytokines such as IFN-γ will preferentially signal to antigenic target cells contacted by the T cell through an immunological synapse. Despite its physiological significance, this prediction has never been tested. We developed a live-cell imaging system to compare the responses of target cells and nonantigenic bystanders to IFN-γ secreted by CD8+, antigen-specific, cytotoxic T cells. Both target cells and surrounding nontarget cells respond robustly. This pattern of response was detected even at minimal antigenic T-cell stimulation using low doses of antigenic peptide, or altered peptide ligands. Although cytotoxic immunological synapses restrict killing to antigenic target cells, the effects of IFN-γ are more widespread.

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“…CTLs express both TCR and CD8, which may bind different sites on the same or different pMHCs (12,18,37). A given TCR is capable of binding different peptides complexed with MHC of the same allele with different kinetic rates and affinities, which can differentially trigger T cell activation (10,11).…”

Section: Isolation Of Mhc-cd8 Binding From the Trimolecular Tcr-mhc-cmentioning

confidence: 99%

Kinetics of MHC-CD8 Interaction at the T Cell Membrane

Huang¹,

Edwards

Evavold

et al. 2007

The Journal of Immunology

118

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CD8 plays an important role in facilitating TCR-MHC interaction, promoting Ag recognition, and initiating T cell activation. MHC-CD8 binding kinetics have been measured in three dimensions by surface plasmon resonance technique using purified molecules. However, CD8 is a membrane-anchored, signaling kinase-linked, and TCR-associated molecule whose function depends on the cell membrane environment. Purified molecules lack their linkage to the membrane, which precludes interactions with other structures of the cell as well as signaling. Furthermore, three-dimensional binding in the fluid phase is biologically and physically distinct from two-dimensional binding across apposing cell membranes. As a first step toward characterizing the molecular interactions between T cells and APCs, we used a micropipette adhesion frequency assay to measure the adhesion kinetics of single mouse T cells interacting with single human RBCs coated with MHC. Using anti-TCR mAb we isolated and characterized the specific two-dimensional MHC-CD8 binding from the trimolecular TCR-MHC-CD8 interaction. The TCR-independent MHC-CD8 interaction has a very low affinity that depends on the MHC alleles, but not on the peptide complexed to the MHC and whether CD8 is an αα homodimer or an αβ heterodimer. Surprisingly, MHC-CD8 binding affinity varies with T cells from different TCR transgenic mice and these affinity differences were abolished by treatment with cholesterol oxidase to disrupt membrane rafts. These data highlight the relevance and importance of two-dimensional analysis of T cells and APCs and indicate that membrane rafts play an important role in modulating the affinity of cell-cell interactions.

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Altered Peptide Ligands Induce Delayed CD8-T Cell Receptor Interaction—a Role for CD8 in Distinguishing Antigen Quality

Cited by 94 publications

References 34 publications

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells

Kinetics of MHC-CD8 Interaction at the T Cell Membrane

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