Interaction between the CD8 Coreceptor and Major Histocompatibility Complex Class I Stabilizes T Cell Receptor-Antigen Complexes at the Cell Surface

Wooldridge, Linda; Berg, Hugo A. van den; Glick, Meir; Gostick, Emma; Laugel, Bruno; Hutchinson, Sarah; Milicic, Anita; Brenchley, Jason M.; Douek, Daniel C.; Price, David A.; Sewell, Andrew K.

doi:10.1074/jbc.m500555200

Cited by 145 publications

(274 citation statements)

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“…2C). This result, in fact, has been observed in experiments by Sewell and coworkers (28), where a panel of MHC class I with mutated CD8 binding sites (11,28,29) was studied. They found that MHC mutants with a 10-fold weaker than WT affinity for CD8 were still able to activate T cells to the same extent (28).…”

Section: Discussionmentioning

confidence: 51%

“…2A shows that changing k off (CD8-MHC) from 60 s −1 to 40 s −1 , which corresponds to a 50% increase in the lifetime of the MHC-CD8 interaction, increases the effective stability of pMHC-TCR interactions by ∼6% (from 41 to 44 s). This has been observed in a panel of mutants that was described above (11,29). In particular, a MHC mutant (Q115E) (11,29) that binds CD8 with ∼50% greater affinity compared with WT was found to improve MHC surface stabilization only by ∼4%.…”

Section: Discussionmentioning

confidence: 88%

“…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).…”

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confidence: 74%

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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: 51%

Section: Discussionmentioning

confidence: 88%

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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 degree to which individual CD8 ϩ T cells depend on the pMHCI/CD8 interaction for stable tetramer binding can be evaluated by using pMHCI tetramers carrying mutations in the ␣ 3 domain that abrogate CD8 binding without affecting TCR recognition (CD8 null ) (51,(63)(64)(65)(66). Fig.…”

Section: Role Of the Cd8 Coreceptor In The Structurally Diverse Tv9 Rmentioning

confidence: 99%

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Schaubert

Price

Frahm

et al. 2007

The Journal of Immunology

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HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p2419–27, TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.

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“…2 CD8 is thought to act as a co-receptor to TCR function; the CD8-MHC-I contact stabilizes the TCR/peptide-MHC-I interaction and increases the TCR triggering rate for low affinity peptide-MHC-I ligands. 3 CD8 cytosolic domains bind to the scr tyrosine protein kinase p56 lck leading to the rapid activation of TCR through the CD3ζ chain tyrosine phosphorylation pathway. 4 Acquisition of cytolytic capability implies expression of effector molecules such as perforin, granzymes and granulysin.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and functional evaluation of CD3+CD4-CD8- T cells in human CD8 immunodeficiency

Bernardo¹,

Mancebo²,

Aguiló³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHuman CD8 immunodeficiency is characterized by undetectable CD8 + lymphocytes and an increased population of CD4 -CD8 -(double negative) T lymphocytes. Design and MethodsWe hypothesized that the double negative subset corresponds to the cellular population that should express CD8 and is committed to the cytotoxic T lymphocyte lineage. To assess this, we determined the phenotype and function of peripheral blood mononuclear cells and/or magnetically isolated double negative T lymphocytes from two CD8-deficient patients. To analyze the expression and co-localization with different organelles, 293T cells were transfected with plasmids bearing wild-type or mutated CD8a. ResultsCD8a mutated protein was retained in the cytoplasm of transfected cells. The percentages of double negative cells in patients were lower than the percentages of CD8 + T cells in healthy controls. Double negative cells mostly had an effector or effector memory phenotype whereas naïve T cells were under-represented. A low concentration of T-cell receptor excision circles together with a skewed T-cell receptor-Vb repertoire were observed in the double negative population. These data suggest that, in the absence of CD8 co-receptor, the thymic positive selection functions suboptimally and a limited number of mature T-cell clones would emerge from the thymus. In vitro, the double negative cells showed a mild defect in cytotoxic function and decreased proliferative capacity. ConclusionsIt is possible that the double negative cells are major histocompatibility complex class-I restricted T cells with cytolytic function. These results show for the first time in humans that the presence of the CD8 co-receptor is dispensable for cytotoxic ability, but that it affects the generation of thymic precursors committed to the cytotoxic T lymphocyte lineage and the proliferation of mature cytotoxic T cells.Key words: CD8 immunodeficiency, double negative T lympho cytes, MHC class-I, cytotoxic T lymphocyte proliferation. 2011;96(8):1195-1203. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Bernardo I, Mancebo E, Aguiló I, Anel A, Allende LM, Guerra-Vales JM, Ruiz-Contreras J, Serrano A, Talayero P, de la Calle O, Gonzalez-Santesteban C, and Paz-Artal E. Phenotypic and functional evaluation of CD3 + CD4 -CD8 -T cells in human CD8 immunodeficiency. Haematologica Phenotypic and functional evaluation of CD3 + CD4 -CD8 -T cells in human CD8 immunodeficiency

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Interaction between the CD8 Coreceptor and Major Histocompatibility Complex Class I Stabilizes T Cell Receptor-Antigen Complexes at the Cell Surface

Cited by 145 publications

References 83 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

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Phenotypic and functional evaluation of CD3+CD4-CD8- T cells in human CD8 immunodeficiency

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