Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

Hamad, Abdel Rahim A.; O'Herrin, Sean M.; Lebowitz, Michael; Srikrishnan, Ananth; Bieler, Joan Glick; Schneck, Jonathan P.; Pardoll, Drew M.

doi:10.1084/jem.188.9.1633

Cited by 98 publications

(80 citation statements)

References 31 publications

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“…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).…”

mentioning

confidence: 58%

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.

165

143

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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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mentioning

confidence: 58%

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.

165

143

View full text Add to dashboard Cite

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“…First, only a portion of the TCRs of a cell localize to the immunological synapse and are thereby involved in the activation process (32). Second, and more importantly, there is considerable evidence that effective signaling via the TCR requires engagement of at least two agonist-MHC complexes by two TCRs creating a TCR oligomer signaling complex (33)(34)(35)(36)(37). Thus, inhibition of activation by a TCR antagonist could be accomplished by preventing only a fraction of the TCRs within the synapse from engaging an agonist peptide.…”

Section: Discussionmentioning

confidence: 99%

“…The P14 TCR is specific for the LCMV epitope GP [33][34][35][36][37][38][39][40][41] , is restricted by D b , and expresses V␤8.1; the OT-1 TCR is specific for OVA [257][258][259][260][261][262][263][264] , is restricted by K b , and expresses V␤5.1. Homozygous P14, rag2 Ϫ/Ϫ , and hemizygous OT-1, rag2 Ϫ/Ϫ mice were bred to generate F 1 (P14/OT-1) mice transgenic for the two TCRs.…”

Section: Characterization Of Dual-tcr-expressing T Cell Linesmentioning

confidence: 99%

Study of the Mechanism of TCR Antagonism Using Dual-TCR-Expressing T Cells

Yang

Grey

2003

The Journal of Immunology

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The mechanism of action of TCR antagonists is incompletely understood. T cells expressing two distinct TCRs have been used to test competition for TCR occupancy as a potential mechanism. Previous studies with CD4 T cells showed that an antagonist for one TCR inhibited the response to the other TCR (cross-antagonism), whereas studies with CD8 cells failed to demonstrate cross-antagonism. To determine whether CD4 and CD8 cells were intrinsically different or whether the differences were the result of the use of different effector assays, we studied both CD4 and CD8 dual-TCR-expressing T cells. In the CD4 system, consistent with previous reports, cross-antagonism of proliferation was observed. In the CD8 system, cross-antagonism was observed using proliferation as readout but not when target cell cytolysis was used. These results suggest that different mechanisms may be involved in the inhibition of proliferation and inhibition of cytotoxic effector function, the latter only involving competition for TCR occupancy. Inhibition of proliferation appears to be more complex and other mechanisms such as sequestration of signaling molecules or negative signaling may be involved. The fact that 10- to 20-fold more antagonist was needed to achieve cross-antagonism compared with inhibition of the cognate TCR is consistent with the hypothesis that competition for TCR occupancy is also a major, albeit not sole, mechanism of antagonism of the proliferative responses of CD4 and CD8 cells.

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“…MHCIgG fusion proteins have been described and studied in vitro (18,(27)(28)(29), and a divalent I-E d molecule fused to an IgG2a Fc was recently shown to induce differentiation of T cells toward a Th2 phenotype (30). MHC-IgG fusion proteins have not, to our knowledge, been used in vivo to inhibit T cell autoimmune responses.…”

mentioning

confidence: 99%

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

Zuo

Cullen

DeLay

et al. 2002

The Journal of Immunology

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T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-Aq fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases.

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Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

Cited by 98 publications

References 31 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

Study of the Mechanism of TCR Antagonism Using Dual-TCR-Expressing T Cells

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

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