Formation of TCR dimers/trimers as a crucial step for T cell activation

Bachmann, Martin F.; Salzmann, Michael; Oxenius, Annette; Ohashi, Pamela S.

doi:10.1002/(sici)1521-4141(199808)28:08<2571::aid-immu2571>3.0.co;2-t

Cited by 44 publications

(29 citation statements)

References 43 publications

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“…Recently activated T cells show reduced TCR surface expression levels (59,60). We therefore reasoned that TCR expression levels might differ in CD62L…”

Section: Cells Have Reduced Surface Tcr Expression Levelsmentioning

confidence: 99%

Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor α and CD62L

Bachmann¹,

Wolint

Schwarz³

et al. 2005

The Journal of Immunology

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245

272

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Three major subsets of Ag-experienced CD8+ T cells have been identified according to their expression of CD62L and CD127. These markers are associated with central memory T cells (CD62L+CD127+), effector memory T cells (CD162L−CD127+), and effector T cells (CD62L−CD127−). In this study we characterized the development of these three populations during acute and chronic viral infections and after immunization with virus-like particles and determined their lineage relation and functional and protective properties. We found that the balance between the three subsets was critically regulated by the availability of Ag and time. After initial down-regulation of CD127, the responding CD8+ T cell population down-regulated CD62L and re-expressed CD127. Dependent on Ag availability, the cells then further differentiated into CD62L−CD127− effector cells or, in the absence of Ag, re-expressed CD62L to become central memory T cells. Although all three populations efficiently produced effector cytokines such as IFN-γ, CD62L−CD127− effector cells exhibited the highest ex vivo lytic potential. In contrast, CD62L+CD127+ central memory T cells most efficiently produced IL-2 and proliferated extensively in vitro and in vivo upon antigenic restimulation. Strikingly, only effector and effector memory, but not central memory, T cells were able to protect against peripheral infection with vaccinia virus, whereas central memory T cells were most potent at protecting against systemic infection with lymphocytic choriomeningitis virus, indicating that the antiviral protective capacities of specific CD8+ T cell subsets are closely related to the nature of the challenging pathogen.

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“…Recently activated T cells show reduced TCR surface expression levels (59,60). We therefore reasoned that TCR expression levels might differ in CD62L…”

Section: Cells Have Reduced Surface Tcr Expression Levelsmentioning

confidence: 99%

Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor α and CD62L

Bachmann¹,

Wolint

Schwarz³

et al. 2005

The Journal of Immunology

Self Cite

245

272

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“…Studies by Zhang et al (18) have shown that TCR-mediated signaling is enhanced upon oligomerization (11). This aggregation of TCR resulting in increased signaling efficiency may be influenced by the recruitment of these receptors into lipid rafts upon engagement with peptide/MHC molecules on APCs (12).…”

mentioning

confidence: 99%

Optimal Colocalization of TCR and CD8 as a Novel Mechanism for the Control of Functional Avidity

Cawthon

Alexander-Miller

2002

The Journal of Immunology

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The improved efficacy of high avidity CTL for clearance of virus has been well-documented. Thus, elucidation of the mechanisms that confer the increased sensitivity to peptide ligand demonstrated by high avidity CTL is critical. Using CTL lines of high and low avidity generated from a TCR transgenic mouse, we have found that functional avidity can be controlled by the expression of CD8αα vs CD8αβ and the ability of CTLs to colocalize the TCR and CD8 in the membrane. Colocalization of these molecules was mediated by lipid rafts and importantly, raft disruption resulted in the conversion of high avidity CTL into a lower functional avidity phenotype. These novel findings provide insights into the control of functional avidity in response to viral infection.

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“…Previous mathematical analysis of T cell responses have been successful in modeling specific features such as fast ligand dissociation kinetics (6), peptide antagonism (7,8), rate of receptor internalization (9), or the effect of co-stimulation on proliferation (10). Current models favor a discrimination between the potency of TCR ligands based on the life-time of the interaction, i.e.…”

Section: Most T Cells Present ␣␤ T Cell Receptors (Tcr)mentioning

confidence: 99%

“…Current models favor a discrimination between the potency of TCR ligands based on the life-time of the interaction, i.e. the off-rate (6,7,9). In Support, recent studies suggest that TCR signaling correlates to ligand dissociation rate (11)(12)(13).…”

Section: Most T Cells Present ␣␤ T Cell Receptors (Tcr)mentioning

confidence: 99%

A Response Calculus for Immobilized T Cell Receptor Ligands

Andersen

Menné

Mariuzza

et al. 2001

Journal of Biological Chemistry

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To address the molecular mechanism of T cell receptor (TCR) signaling, we have formulated a model for T cell activation, termed the 2D-affinity model, in which the density of TCR on the T cell surface, the density of ligand on the presenting surface, and their corresponding two-dimensional affinity determine the level of T cell activation. When fitted to T cell responses against purified ligands immobilized on plastic surfaces, the 2D-affinity model adequately simulated changes in cellular activation as a result of varying ligand affinity and ligand density. These observations further demonstrated the importance of receptor cross-linking density in determining TCR signaling. Moreover, it was found that the functional two-dimensional affinity of TCR ligands was affected by the chemical composition of the ligandpresenting surface. This makes it possible that cellbound TCR ligands, despite their low affinity in solution, are of optimal two-dimensional affinity thereby allowing effective TCR binding under physiological conditions, i.e. at low ligand densities in cellular interfaces. Most T cells present ␣␤ T cell receptors (TCR)1 on their surface. The natural ligands for these receptors are small antigenic peptides bound to MHC molecules (pep⅐MHC) on the surface of other cells with which T cells interact (1). Antigen recognition can result in various protective functions, including release of cytokines to cause local inflammation and specific killing of virus-infected cells (2).The TCR comprises the ␣/␤ subunits that recognize pep⅐MHC and the signal-transducing subunits ␦, ⑀, ␥, and (CD3-complex), which contain the immunoreceptor tyrosinebased activation motifs (ITAMs) (3). Signaling of the TCR⅐CD3-complex can be viewed as a dynamic phosphorylation/dephosphorylation equilibrium of ITAMs where the steady-state levels of phosphorylated ITAMs are low in unstimulated T cells (4). The molecular mechanism by which ligand-bound TCR perturbs this equilibrium is unknown.One way to help identify the molecular features underlying TCR signaling is to develop mathematical models capable of simulating TCR signaling. Describing TCR signaling as a dynamic equilibrium indicates that it should be possible to model T cell behavior using mathematical expressions involving the binding constants of TCR⅐ligand interactions. Moreover, as recently discussed (5), such models are attractive because they allow for simulation of T cell responses and thus help guide future research, and because they can assist in optimizing clinical immunomodulatory strategies.Previous mathematical analysis of T cell responses have been successful in modeling specific features such as fast ligand dissociation kinetics (6), peptide antagonism (7, 8), rate of receptor internalization (9), or the effect of co-stimulation on proliferation (10). Current models favor a discrimination between the potency of TCR ligands based on the life-time of the interaction, i.e. the off-rate (6, 7, 9). In Support, recent studies suggest that TCR signaling correlates to ligand disso...

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Formation of TCR dimers/trimers as a crucial step for T cell activation

Cited by 44 publications

References 43 publications

Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor α and CD62L

Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor α and CD62L

Optimal Colocalization of TCR and CD8 as a Novel Mechanism for the Control of Functional Avidity

A Response Calculus for Immobilized T Cell Receptor Ligands

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