Influence of Human CD8 on Antigen Recognition by T-Cell Receptor–Transduced Cells

Lyons, Gretchen E.; Moore, Tamson V.; Brasic, Natasha; Li, Mingli; Roszkowski, J; Nishimura, Michael I.

doi:10.1158/0008-5472.can-06-2379

Cited by 39 publications

(44 citation statements)

References 43 publications

(85 reference statements)

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“…In contrast, disruption of the synergistic extracellular binding effects and intracellular coreceptor functions of CD8 in the system of Holler and Kranz probably resulted in a higher stringency of coreceptor dependence. A recent study suggested that the signaling properties of CD8 act in synergy with the TCR/pMHCI stabilization effect and are likely to have a dominant effect in the overall enhancement of the antigen sensitivity phenomenon conferred by the coreceptor (49). The difference of coreceptor dependence affinity thresholds observed in our study and in that of Holler and Kranz fits well with this concept.…”

Section: Discussionsupporting

confidence: 88%

Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties

Laugel

Berg

Gostick

et al. 2007

Journal of Biological Chemistry

204

325

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T cells have evolved a unique system of ligand recognition involving an antigen T cell receptor (TCR) and a coreceptor that integrate stimuli provided by the engagement of peptide-major histocompatibility complex (pMHC) antigens. Here, we use altered pMHC class I (pMHCI) molecules with impaired CD8 binding (CD8-null) to quantify the contribution of coreceptor extracellular binding to (i) the engagement of soluble tetrameric pMHCI molecules, (ii) the kinetics of TCR/pMHCI interactions on live cytotoxic T lymphocytes (CTLs), and (iii) the activation of CTLs by cell-surface antigenic determinants. Our data indicate that the CD8 coreceptor substantially enhances binding efficiency at suboptimal TCR/pMHCI affinities through effects on both association and dissociation rates. Interestingly, coreceptor requirements for efficient tetramer labeling of CTLs or for CTL activation by determinants displayed on the cell surface operated in different TCR/pMHCI affinity ranges. Wild-type and CD8-null pMHCI tetramers required monomeric affinities for cognate TCRs of K D < ϳ80 M and ϳ35 M, respectively, to label human CTLs at 37°C. In contrast, activation by cellular pMHCI molecules was strictly dependent on CD8 binding only for TCR/pMHCI interactions with K D values >200 M. Altogether, our data provide information on the binding interplay between CD8 and the TCR and support a model of CTL activation in which the extent of coreceptor dependence is inversely correlated to TCR/pMHCI affinity. In addition, the results reported here define the range of TCR/pMHCI affinities required for the detection of antigen-specific CTLs by flow cytometry.In concert with the T cell receptor (TCR), 3 the coreceptors CD4 and CD8 participate in and enhance the process of antigen recognition by T cells through extracellular interactions with peptide-major histocompatibility complex (pMHC) molecules (1-3) and amplification of ensuing signal transduction events (4 -8). CD8 molecules are predominantly expressed as ␣␤ heterodimers on the surface of cytotoxic T lymphocytes (CTLs) (9), but are also found in ␣␣ homodimeric form on intraepithelial ␣␤ T lymphocytes, certain subsets of circulating activated CTLs, and the membranes of distinct cell lineages such as ␥␦ T cells, natural killer T cells, and dendritic cells (reviewed in Ref. 10). CD8␣␣ and CD8␣␤ bind directly to invariant domains of major histocompatibility complex class I (MHCI) molecules (11-13). Although CD8␣␣ and CD8␣␤ bind MHCI molecules with similar affinities (14), it is well established that CD8␣␣ is a much poorer coreceptor for CTLs than is CD8␣␤. Indeed, an emerging concept is that CD8␣␣ acts as an inhibitor of CTL activation (10). More generally, recent experimental evidence has lent credence to the hypothesis that efficient regulation of CTL activity is mediated by modifications of CD8 coreceptor functions in vivo. These modifications include switching to expression of the CD8␣␣ homodimer, post-translational changes of CD8␣␤ following activation (15, 16), and downregulation of CD8 expres...

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Section: Discussionsupporting

confidence: 88%

Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties

Laugel

Berg

Gostick

et al. 2007

Journal of Biological Chemistry

204

325

View full text Add to dashboard Cite

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“…Generation of CD8 + Jurkat cells has been described previously (19,47). Briefly, a modified SAMEN retroviral vector containing full-length human CD8 α and β, separated by an internal SRα promoter, and an internal ribosome entry site/neo r cassette was used to transduce cells.…”

Section: Discussionmentioning

confidence: 99%

“…Jurkat cells, CD8 + Jurkat cells, and anti-CD3-activated primary T cells were transduced to express HCV1406 TCR via spinoculation, as previously described (20,22,47,48). Briefly, 0.5 mL per well of 30 μg/mL retronectin was used to coat 24-well, flat-bottom, nontissue culture-treated plates overnight at 4°C.…”

Section: Discussionmentioning

confidence: 99%

How an alloreactive T-cell receptor achieves peptide and MHC specificity

Wang

Singh

Spear

et al. 2017

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

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T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 − individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.T-cell receptor | peptide-MHC | structure | alloreactivity | specificity

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“…phorbol myristate acetate, PMA), for maximal IL-2 production. Jurkat cells expressing tyrosinase-specific TCR and αβCD8, α′β′CD8 or no CD8 were prepared as described [16]. T2 cells are a Tap-1 −/− human B/T cell lymphoma.…”

Section: Methodsmentioning

confidence: 99%

CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Zloza

Jagoda

Lyons

et al. 2010

Cancer Immunol Immunother

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CD8+ T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-β have been studied individually, the influence of CD8 co-receptor on TGF-β function in CD8+ T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-β-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no αβCD8 molecule, we demonstrate that cells expressing full-length αβCD8 were highly susceptible, αβCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-β. Additionally, we determined that inhibition of Lck rendered mouse CD8+ T cells highly resistant to TGF-β suppression. Resistance was not associated with TGF-β receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8+ T cells for response to TGF-β. Based on the important role which TGF-β-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8+ T cell-related cancer immunotherapy strategies.

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Influence of Human CD8 on Antigen Recognition by T-Cell Receptor–Transduced Cells

Cited by 39 publications

References 43 publications

Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties

Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties

How an alloreactive T-cell receptor achieves peptide and MHC specificity

CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

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