Minimal requirements for peptide mediated activation of CD8+ CTL

Brower, Richard C.; England, Roger; Takeshita, Toshiyuki; Kozlowski, Steven; Margulies, David H.; Berzofsky, Jay A.; DeLisi, Charles

doi:10.1016/0161-5890(94)90079-5

Cited by 66 publications

(41 citation statements)

References 19 publications

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“…One of the factors contributing to CTL avidity is the affinity of the TCR. One might speculate that the onset of lysis requires some threshold number of TCR molecules to be engaged or aggregated (39) or to be serially triggered (40,41). In either case, since low-affinity TCRs would be expected to have a much shorter average dwell time for engagement of the peptide-MHC complex than that of high-affinity TCRs, the probability that an encounter between a TCR and its ligand would last long enough to result in a productive signal would be lower for low-avidity CTL.…”

Section: Discussionmentioning

confidence: 99%

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

Derby

Alexander-Miller

Tse

et al. 2001

The Journal of Immunology

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Previously, we observed that high-avidity CTL are much more effective in vivo than low-avidity CTL in elimination of infected cells, but the mechanisms behind their superior activity remained unclear. In this study, we identify two complementary mechanisms: 1) high-avidity CTL lyse infected cells earlier in the course of a viral infection by recognizing lower Ag densities than those distinguished by low-avidity CTL and 2) they initiate lysis of target cells more rapidly at any given Ag density. Alternative mechanisms were excluded, including: 1) the possibility that low-avidity CTL might control virus given more time (virus levels remained as high at 6 days following transfer as at 3 days) and 2) that differences in efficacy might be correlated with homing ability. Furthermore, adoptive transfer of high- and low-avidity CTL into SCID mice demonstrated that transfer of a 10-fold greater amount of low-avidity CTL could only partially compensate for their decreased ability to eliminate infected cells. Thus, we conclude that high-avidity CTL exploit two complementary mechanisms that combine to prevent the spread of virus within the animal: earlier recognition of infected cells when little viral protein has been made and more rapid lysis of infected cells.

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Section: Discussionmentioning

confidence: 99%

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

Derby

Alexander-Miller

Tse

et al. 2001

The Journal of Immunology

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195

170

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“…Because monomeric TCR engagement is ineffective in activating CD8 ϩ T cells, it seems reasonable to conclude that CD8 ϩ T cell triggering is due to TCR clustering, as seen for CD4 ϩ T cells. However, we do not know how many represented peptides are needed per cell for effective representation, and there remain important differences between the activation of CD8 ϩ and CD4 ϩ T cells, particularly with regard to the minimal peptide-MHC density required on conventional presenting cells to induce T cell activation processes (11,(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Soluble peptide–MHC monomers cause activation of CD8⁺T cells through transfer of the peptide to T cell MHC molecules

Stone

Thompson

et al. 2002

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

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T cell receptor (TCR)-mediated activation of CD4 ؉ T cells is known to require multivalent engagement of the TCR by, for example, oligomeric peptide-MHC complexes. In contrast, for CD8 ؉ T cells, there is evidence for TCR-mediated activation by univalent engagement of the TCR. We have here compared oligomeric and monomeric L d and K b peptide-MHC complexes and free peptide as stimulators of CD8 ؉ T cells expressing the 2C TCR. We found that the monomers are indeed effective in activating naïve and effector CD8 ؉ T cells, but through an unexpected mechanism that involves transfer of peptide from soluble monomers to T cell endogenous MHC (K b ) molecules. The result is that T cells, acting as antigenpresenting cells, are able to activate other naïve T cells.CD8 ϩ T lymphocytes ͉ T cell receptor ͉ major histocompatibility complex ͉ antigen presentation ͉ lymphocyte activation A ntigen-driven activation of cells of the immune system generally involves multivalent antigen engagement that leads to clustering or ''crosslinking'' of cell-surface receptors. This concept arose largely from observations of antigen-induced capping of surface immunoglobulins on B cells (1, 2) and multivalent antigen triggering of histamine release from mast cells (3). Whether multivalent engagement of T cell antigen receptors (TCR) is required to initiate T cell activation has been difficult to determine, primarily because the antigens are peptide-MHC complexes normally found as integral membrane proteins on the surfaces of other cells. However, experiments using soluble recombinant MHC molecules lacking transmembrane domains and carrying defined synthetic peptides have shown clearly that peptide-MHC oligomers, but not monomers, can activate CD4 ϩ T cells (4-7). Thus, for CD4 ϩ T cells, multivalent engagement of TCR is sufficient to initiate cellular activation, whereas monovalent engagement is apparently nonproductive.For CD8 ϩ T cells, however, the issue remains unclear. Several studies have found that multivalent engagement is required to activate these cells (4, 8-10), but some evidence suggests the sufficiency of monovalent TCR engagement to trigger a cytolytic response, such as the requirement for such a small number of peptide-MHC complexes per target cell in cytolytic assays, to imply that a single complex can trigger the cytolytic response in CD8 T cells (11). Activation of CD8 ϩ T cells by soluble peptide-MHC monomers has been clearly observed in the presence of CD8 molecules (12, 13). It was suggested from that result that monovalent engagement of TCR can serve as the initiating event when it results in TCR association with CD8 (12). However, in another study, TCR-CD8 heterodimerization induced by peptide-MHC monomers was observed but was found not to activate the cells (9).In this study, we investigated the requirements for initiating signaling processes in naïve and activated CD8 ϩ T cells carrying the 2C TCR. The 2C TCR recognizes various peptide-MHC complexes, including (i) the potent allogenic activator Materials and Methods...

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“…Early studies estimated that anywhere from 1-400 peptides per antigen-presenting cell were needed to fully activate a T-cell [2][3][4][5][6][7] . More recent studies using soluble pMHC dimers suggest that, at least for CD4 + T-cells, a dimer or trimer of agonist pMHC was needed for full T-cell activation 8,9 .…”

Section: The Basic Unit Of Tcr Signaling: Models Of T-cell Activationmentioning

confidence: 99%

A role for “self” in T-cell activation

Krogsgaard

Juang

Davis

2007

Seminars in Immunology

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The mechanisms by which αβ T cells are selected in the thymus and then recognize peptide MHC (pMHC) complexes in the periphery remain an enigmatic. Recent work particularly with respect to quantification of T-cell sensitivity and the role of self-ligands in T-cell activation has provided some important clues to the details of how TCR signaling might be initiated. Here, we highlight recent experimental data that provides insights into the initiation of T-cell activation and also discuss the main controversies and uncertainties in this area.

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Minimal requirements for peptide mediated activation of CD8+ CTL

Cited by 66 publications

References 19 publications

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

Soluble peptide–MHC monomers cause activation of CD8⁺T cells through transfer of the peptide to T cell MHC molecules

A role for “self” in T-cell activation

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Minimal requirements for peptide mediated activation of CD8+ CTL

Cited by 66 publications

References 19 publications

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

Soluble peptide–MHC monomers cause activation of CD8+T cells through transfer of the peptide to T cell MHC molecules

A role for “self” in T-cell activation

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Soluble peptide–MHC monomers cause activation of CD8⁺T cells through transfer of the peptide to T cell MHC molecules