Differences in antigen recognition and cytolytic activity of CD8<sup>+</sup>and CD8<sup>−</sup>T cells that express the same antigen-specific receptor

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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...

Section: Activation By Soluble Monomers Requires the Presence Of Endosupporting

confidence: 81%

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

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“…Thus, even for CD8, the main effect of the coreceptor is to enhance Lck recruitment to the TCR complex, and for CD4 it is the only effect. The importance of CD8-mediated Lck recruitment for T-cell activation is also indicated by data showing that CD8 − and CD8 + T cells are indistinguishable for T-cell activation by allogeneic MHC alleles (20).…”

Section: Resultsmentioning

confidence: 89%

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Artyomov

Lis

Devadas

et al. 2010

173

144

The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptidemajor histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR-pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr-pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function.M embrane proteins CD4 and CD8 are expressed on T helper cells and cytotoxic T lymphocytes, respectively, that are known to augment the sensitivity and response of T cells to cognate peptide-major histocompatibility (pMHC) ligands (1-3). It is generally thought that the ability of these coreceptors to enhance T-cell responses is due to two main effects: (i) Binding of CD4 and CD8 to MHC class II and class I molecules helps stabilize weak T-cell receptor (TCR)-pMHC interactions; and (ii) the Src kinase, Lck, which is bound to the cytoplasmic tail of coreceptors, is efficiently recruited to the TCR complex upon coreceptor binding to the MHC, thereby enhancing the initiation of TCR signaling (3, 4).Surface plasmon resonance (SPR) analyses show that the halflives characterizing coreceptor-MHC interactions are <35 ms (off rate >20 s −1 , the resolution of SPR instruments) for both CD4 and CD8 (5-7). It is difficult to understand how the two effects noted above can be potentiated by such fleeting interactions. For example, consider the effect of coreceptor-MHC interactions in stabilizing the TCR-pMHC complex. A typical agonist pMHC ligand is bound to a TCR for ≈10,000 ms (corresponding to an off rate of 0.1 s −1 ) (8). Thus, during the lifetime of the TCR-pMHC bond a coreceptor would disengage from the MHC ≈1,000 times, making it implausible that stabilization of TCR-pMHC interactions would be achieved. Recent data measuring TCR binding within a synapse (9) show that it is less stable, perhaps 1,000 ms for an average TCR-ligand interaction due to actin polymerization activity, but this is still far in excess of what has been reported for CD4 and CD8 interactions.However, CD8 has been found to stabilize pMHC binding to CD8+ T-cell surfaces (10, 11) and augment sensitivity (2, 12). In contrast, past studies (13,14) and recent in situ measurements at intercellular junctions show that CD4 does not stabilize the interactions of TCR with class II pMHC molecules (9). However, CD4 does enhance the sensitivity of T helper cells (1,9,15,16). As the binding affinity of CD4 for the MHC ectodomain has been reported to be ...

“…The anti-CD8 antibody used here (2.43) was shown to decrease markedly a cloned 2C T cell cytolytic response to a relatively weak agonist (SIY/K b ) but hardly to reduce this response to a strong agonist (QL9/L d ) (21).…”

Section: Methodsmentioning

confidence: 99%

“…Nevertheless, mature 2C T cells that lack CD4 and CD8 can make robust pMHCspecific responses to APC that present highly potent pMHC agonists (Fig. 1C) (21). Moreover, after infection with various pathogens, CD4 Ϫ/Ϫ mice produce CD8 ϩ T cells that react specifically with strong pMHC-II agonists (50,51).…”

Section: Discussionmentioning

confidence: 99%

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Stage-dependent reactivity of thymocytes to self-peptide–MHC complexes

Leng

Nguyen

et al. 2007

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