Cutting Edge: Positive Selection Induced by a Self-Peptide with TCR Antagonist Activity

Santori, Fabio R.; Brown, Stuart M.; Lu, Yuanyao; Neubert, Thomas A.; Vukmanović, Stanislav

doi:10.4049/jimmunol.167.11.6092

Cited by 15 publications

(23 citation statements)

References 35 publications

(40 reference statements)

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“…In accordance with the findings of the other groups who identified self-peptides capable of positively selecting thymocytes [2][3][4][5], one of the self-peptides we identified was derived from a ubiquitously expressed gene. Collectively these data suggest that the self-peptides presented in the thymus that mediate positive selection of the T cell repertoire are also found and presented in the periphery.…”

Section: Discussionsupporting

confidence: 74%

“…The nature of these self-peptide complexes has been the focus of several studies. Collectively, these studies provide strong evidence that positive selection can be mediated by ubiquitously expressed self-peptides that contain no significant homology to the cognate peptide of the selected TCR [2][3][4][5][6]. If T cells are indeed selected on ubiquitously expressed self-peptides, then the potential for selfreactivity in the periphery exists.…”

Section: Introductionmentioning

confidence: 99%

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Weak agonist self‐peptides promote selection and tuning of virus‐specific T cells

et al. 2003

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Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H-2D b and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select the virus-specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse-phase HPLC and mass spectrometry demonstrated that these peptides were presented by H-2D b molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM-selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP-selected T cells only retained their ability to respond to high concentrations of RPP. These results demonstrate that self-peptides that mediate positive selection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Weak agonist self‐peptides promote selection and tuning of virus‐specific T cells

et al. 2003

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“…1, PMA at a concentration of 1.0 ng/ml, but not 0.5 ng/ml, induced coreceptor down-modulation in H-Y TCR transgenic, RAG-2 Ϫ/Ϫ thymocytes on a nonselecting background (H-2 d ). Similarly, culture of the same thymocytes with a self-peptide, Ube1x 509 -517 , capable of inducing positive selection (17) failed to induce coreceptor down-modulation (Fig. 1).…”

Section: Synergistic Action Of Self-peptide and Suboptimal Doses Of Pmentioning

confidence: 99%

“…After 3-4 days mice were killed, and the activated macrophages were collected with cold PBS. The cells were washed, resuspended in PM medium (17) supplemented with 20% FCS and plated in flat-bottom, 96-well plates at a density of 2 ϫ 10 5 cells/well. Macrophages were incubated for at least 1 h at 37°C, then they received 4 ϫ 10 5 thymocytes/well derived from either male or female HYB10.D2 RAG Ϫ/Ϫ mice.…”

Section: Coreceptor Down Modulation Dulling Assaymentioning

confidence: 99%

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Delineation of Signals Required for Thymocyte Positive Selection

Santori

Vukmanović

2004

The Journal of Immunology

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Peptide/MHC complexes capable of inducing positive selection in mouse fetal thymic organ cultures fail to do so in suspension culture. Furthermore, this type of culture does not promote initial stages of differentiation, such as coreceptor down-modulation, unless peptides used for stimulation have (at least) weak agonist activity. We show in this study that signals provided in suspension culture by nonagonist peptide/MHC complexes on the surface of macrophages, even though apparently silent, are sufficient to promote complete phenotypic differentiation when CD4+CD8+ thymocytes are subsequently placed in a proper anatomical setting. Furthermore, the synergistic actions of suboptimal concentrations of phorbol esters and nonagonist peptide/MHC complexes can make the initial stages of positive selection visible, without converting maturation into negative selection. Thus, the correlation between efficiency of positive selection and the degree of coreceptor down-modulation on CD4+CD8+ thymocytes is not linear. Furthermore, these results suggest that the unique role of thymic stromal cells in positive selection is related not to presentation of self-peptide/MHC complexes, but most likely to another ligand.

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The CD3 γϵ/δϵ signaling module provides normal T cell functions in the absence of the TCR ζ immunoreceptor tyrosine‐based activation motifs

et al. 2005

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T cell receptor (TCR) signal transduction is mediated by the immunoreceptor tyrosine-based activation motifs (ITAM). The ten ITAM in the TCR complex are distributed in two distinct signaling modules termed TCR zetazeta and CD3 gammaepsilon/deltaepsilon. To delineate the specific role of the zeta ITAM in T cell development and TCR signal transmission, we compared the properties of T cells from different TCR zeta-transgenic lines wherein tyrosine-to-phenylalanine substitutions had been introduced in the zeta subunit. These lines lack selected phosphorylated forms of TCR zeta including just p23, both p21 and p23, or all phospho-zeta derivatives. We report herein that the efficiency of positive selection in HY TCR-transgenic female mice was directly related to the number of zeta ITAM in the TCR. In contrast, TCR-mediated signal transmission and T cell proliferative responses following agonist peptide stimulation were similar and independent of the zeta ITAM. Only the duration of MAPK activation was affected by multiple zeta ITAM substitutions. These results strongly suggest that the ITAM in the CD3 gammaepsilon/deltaepsilon module can provide normal TCR signal transmission, with zeta ITAM providing a secondary function facilitating MAPK activation and positive selection.

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Cutting Edge: Positive Selection Induced by a Self-Peptide with TCR Antagonist Activity

Cited by 15 publications

References 35 publications

Weak agonist self‐peptides promote selection and tuning of virus‐specific T cells

Weak agonist self‐peptides promote selection and tuning of virus‐specific T cells

Delineation of Signals Required for Thymocyte Positive Selection

The CD3 γϵ/δϵ signaling module provides normal T cell functions in the absence of the TCR ζ immunoreceptor tyrosine‐based activation motifs

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