Cutting Edge: Inhibitory Effects of CD4 and CD8 on T Cell Activation Induced by High-Affinity Noncognate Ligands

Chervin, Adam S.; Stone, Jon R.; Bowerman, Natalie A.; Kranz, David M.

doi:10.4049/jimmunol.0901664

Cited by 10 publications

(20 citation statements)

References 29 publications

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“…[45][46][47] Lck sequestration from the TCR/CD3 complex plays a role in T cell-positive selection in the thymus, 48 and it has been proposed to regulate ongoing immune responses and to help maintain peripheral tolerance and MHC restriction. [49][50][51] The present findings indicate that coreceptor tuning for MHC-I-restricted T lymphocytes is not only regulated by levels of CD8 on the T cells, but also by the overall levels of MHC-I on the APCs. While low levels of noncognate MHC-I may enhance APC/T-cell interactions by facilitating cell-to-cell adhesion, 52 high levels of noncognate MHC-I decrease T-cell activation.…”

Section: Discussionmentioning

confidence: 55%

Interferon γ limits the effectiveness of melanoma peptide vaccines

Cho

Lee

Celis

2011

Blood

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IntroductionBecause cytotoxic T lymphocytes (CTLs) have the ability to recognize and kill tumor cells, considerable efforts are being devoted to the development of T-cell immunotherapies for cancer. [1][2][3] CTLs express the CD8 coreceptor and recognize antigen on tumor cells as peptide/major histocompatibility class I (MHC-I) complexes. As a consequence of antigen recognition, CD8 CTLs exert antitumor function via the perforin-granzyme cytolytic pathway or through cytokines such as interferon gamma (IFN␥) and tumor necrosis factor alpha (TNF␣), which exhibit cytostatic activity. The MHC-I-binding peptides recognized by tumorreactive CD8 T lymphocytes are usually derived from genes preferentially expressed by transformed cells or from tissuedifferentiation antigens. The identification of MHC-I-binding peptides that serve as tumor-rejection CD8 T-cell epitopes has opened the door to developing synthetic peptide cancer vaccines. 4 The discovery of melanoma T-cell epitopes for humans and mice has led to studies assessing the utility of peptide vaccines for the treatment of established disease states. In many of these studies, promising, but ultimately not outstanding, therapeutic effects were attained, indicating that the use of synthetic peptides alone, with commonly used adjuvants such as incomplete Freund adjuvant, or in combination with cytokines constitute relatively weak and ineffective vaccines. [5][6][7][8] Thus, several groups, including ours, have focused on optimizing peptide vaccines with the use of Toll-like receptor agonists and costimulatory antibodies as immunologic adjuvants. [9][10][11][12][13][14] Our goal was to design a peptide immunization strategy that generates T-cell responses similar to those observed during an acute viral infection, in which 10% to 50% of all CD8 T cells are specific for the pathogen. We recently described a vaccine that we call TriVax (named for its 3 components: synthetic peptide, polyriboinosinic-polyribocytidylic acid [poly-IC], and anti-CD40 antibody), which achieved our stated goal. 15,16 In addition to generating large CD8 T-cell responses to a melanosomal epitope (Trp2 180 ), significant therapeutic effects (60% long-term survival) were observed against 3-day established B16 melanomas. The therapeutic effect of TriVax disappeared when CD8 T cells were depleted with antibodies or in perforin-deficient mice. Conversely, the elimination of CD4 T lymphocytes and natural killer cells had no significant effect. 16 These results indicated that the major effector mechanism of TriVax is mediated by classic CD8 CTLs through perforin-mediated lysis of tumor cells. Nevertheless, the therapeutic effect of TriVax decreased if vaccination was administered in more advanced disease states, even though large numbers of functional CD8 T cells were detected in the tumor-bearing mice, suggesting that immune-suppressive activity at the tumor site was responsible for the tumor's evasion from the T cells. During these studies, we observed that the therapeutic effectiveness of TriVax was...

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Section: Discussionmentioning

confidence: 55%

Interferon γ limits the effectiveness of melanoma peptide vaccines

Cho

Lee

Celis

2011

Blood

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“…A study by Holler & Kranz 4 showed that CD8 generally increased the pMHC complex potency (reduced the EC 50 ). At the extremes, high-affinity pMHC complexes were found to be sufficiently stimulatory without CD8, and pMHC complexes with low affinities (K d > 3 μM) require CD8 in order to stimulate T cells 4,62 . These effects are not a result of cooperative binding, as it has been shown that the binding of TCR and co-receptors to pMHC complexes are independent 63,64 .…”

Section: Altered Peptide Ligandsmentioning

confidence: 99%

Phenotypic models of T cell activation

et al. 2014

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“…When the T cells were stained with SIY/K b streptavidin-linked tetramers, no staining was observed with mock T cells, but the majority (60 to >80%) of m33 TCR-transduced and m33 TCR-SCS-transduced T cells were stained. The enhanced affinity of the m33 TCR allows efficient staining with soluble SIY/K b tetramer even in CD4 T cells as it does not require CD8 for binding or activity [25,28]. The surface levels of the TCR-SCS construct were 2- to 5-fold higher than the conventional αβ TCR on the transduced C57BL/6 T cells, consistent with our previous studies using the αβ-negative T cell hybridoma 58 −/− [23].…”

Section: Resultsmentioning

confidence: 99%

“…The m33 full-length TCR, with an affinity of 30nM for SIY/K b [34,28], responds to its target in CD4 or co-receptor negative T cells [25]. Likewise, m33 TCR-SCS was functional in CD4 or CD8 T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous results have shown that such Cβ-containing constructs also have potential to mispair as the energy of dimer association is driven largely by C:C region interactions [23]. Finally, while there is strong evidence that TCRs with higher affinity for a class I pepMHC antigen can mediate enhanced effectiveness of CD4 T cell responses because the TCRs are “CD8-independent” [25-27], some of these TCRs also cross-react with self peptides in a CD8-dependent process; these can lead to self-reactive CD8 T cells [28], or to complete deletion of the CD8 T cells [29,30]. …”

Section: Introductionmentioning

confidence: 99%

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A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control

Stone

Harris

Soto

et al. 2014

Cancer Immunol Immunother

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Adoptive transfer of genetically modified T cells to treat cancer has shown promise in several clinical trials. Two main strategies have been applied to redirect T cells against cancer: 1) introduction of a full-length T cell receptor (TCR) specific for a tumor-associated peptide-MHC, or 2) introduction of a chimeric antigen receptor (CAR), including an antibody fragment specific for a tumor cell surface antigen, linked intracellularly to T cell signaling domains. Each strategy has advantages and disadvantages for clinical applications. Here, we present data on the in vitro and in vivo effectiveness of a single-chain signaling receptor incorporating a TCR variable fragment as the targeting element (referred to as TCR-SCS). This receptor contained a single-chain TCR (Vβ-linker-Vα) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3ζ. This format avoided mispairing with endogenous TCR chains, and mediated specific T cell activity when expressed in either CD4 or CD8 T cells. TCR-SCS-transduced CD8-negative cells showed an intriguing sensitivity, compared to full-length TCRs, to higher densities of less stable pepMHC targets. T cells that expressed this peptide-specific receptor persisted in vivo, and exhibited polyfunctional responses. Growth of metastatic antigen-positive tumors was significantly inhibited by T cells that expressed this receptor, and tumor cells that escaped were antigen loss variants. TCR-SCS receptors represent an alternative targeting receptor strategy that combines the advantages of single-chain expression, avoidance of TCR chain mispairing, and targeting of intracellular antigens presented in complex with MHC proteins.

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Cutting Edge: Inhibitory Effects of CD4 and CD8 on T Cell Activation Induced by High-Affinity Noncognate Ligands

Cited by 10 publications

References 29 publications

Interferon γ limits the effectiveness of melanoma peptide vaccines

Interferon γ limits the effectiveness of melanoma peptide vaccines

Phenotypic models of T cell activation

A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control

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