Transient alteration of T cell fine specificity by a strong primary stimulus correlates with T cell receptor down-regulation

Martin, Stefan F.; Bevan, Michael J.

doi:10.1002/(sici)1521-4141(199810)28:10<2991::aid-immu2991>3.0.co;2-b

Cited by 22 publications

(10 citation statements)

References 56 publications

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“…We observed a greater loss of CD3 expression when anti-CD3 stimulation was augmented by cocross-linking CD28 or adding monocytic APC, suggesting that the extent of CD3 down-regulation may be regulated by signal strength as shown in studies of TCR down-regulation in T-cell clones treated with peptide agonists and antagonists. 44 Because it is difficult to isolate antigen-specific effector T cells without defined major histocompatibility complex (MHC) class II-tetramer reagents, we are currently examining whether CD3 loss occurs in human effector CD4 T cells generated by alloantigen stimulation. There are at least 3 possibilities to account for the apparent loss of CD3 expression in effector T cells; first, CD3 may partition to another portion of the cell; second, CD3 may be degraded, and finally, CD3 may be continuously and rapidly recycled through the endocytic compartment.…”

Section: Discussionsupporting

confidence: 74%

Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Krishnan

Warke

Nambiar

et al. 2001

Blood

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Human effector T cells have been difficult to isolate and characterize due to their phenotypic and functional similarity to the memory subset. In this study, a biochemical approach was used to analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon ␥ (IFN-␥) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of CD3 and CD3⑀ signaling subunits coincident with a reduction in surface T-cell receptor (TCR) expression. Because loss of CD3 has also been detected in T cells isolated ex vivo from individuals with cancer, chronic viral infection, and autoimmune diseases, the requirements and kinetics of CD3 down-regulation were examined. The loss of CD3 expression persisted throughout the course of effector T-cell differentiation, was reversible on removal from the activating stimulus, and was modulated by activation conditions. These biochemical changes occurred in effector T cells generated from naive or memory CD4 T-cell precursors and distinguished effector from memory T cells. The results suggest that human effector T-cell differentiation is accompanied by alterations in the TCR signal transduction and that loss of CD3 expression may be a feature of chronic T-cell activation and effector gen- IntroductionThe initiation of adaptive immune responses depends on the activation and differentiation of naive T cells into effector cells that migrate to antigenic sites to orchestrate immune-mediated antigen clearance. Effector T cells can also predominate in diseases characterized by chronic immune activation, such as the autoimmune diseases systemic lupus erythematosus (SLE) 1 and rheumatoid arthritis, 2 and chronic viral infections, 3 and during acute rejection of transplanted tissue. 4 Thus, characterization of the effector T-cell subset at the mechanistic level is essential to understand its role in normal and pathologic immune states.Effector T-cell differentiation involves a series of profound cellular and molecular changes, including an increase in size, up-regulation of activation/differentiation markers such as CD69, CD25, and CD45RO, 5 transcription of effector cytokine genes such as interferon ␥ (IFN-␥) and interleukin-4 (IL-4), 6 and reconfiguring of chromatin structure in the regions of these differentially expressed genes. 7 In contrast to naive CD4 T-cell precursors, the resultant effector CD4 T cells produce high levels of effector cytokines, can be reactivated in the absence of costimulation, 8,9 and exhibit an increased susceptibility to apoptosis. 8 The disparate functions and activation requirements of effector and naive CD4 T cells suggest that distinct signals are being transduced th...

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Section: Discussionsupporting

confidence: 74%

Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Krishnan

Warke

Nambiar

et al. 2001

Blood

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“…The Nature and Dose of the Ligand Determines the Sensitivity of Antibody-induced TCR Down-modulation to PTK Inhibitors-Conflicting results have been obtained from different studies on the PTK dependence of antibody-induced TCR downmodulation (15)(16)(17)(18)(19). One reason for such variation could be the use of soluble or immobilized (plate-bound) antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…Some studies suggest that the TCR internalization and down-modulation are protein-tyrosine kinase (PTK)-dependent processes that ultimately result in the degradation of the TCR (5,(15)(16)(17). However, in other studies PTK inhibitors did not affect TCR downmodulation (18,19).…”

Section: Regulation Of Tcrmentioning

confidence: 99%

“…We previously demonstrated that at high concentrations of MHCp, the TCR is down-regulated by a PTK-independent mechanism, whereas TCR down-modulation was completely abrogated by a PTK inhibitor at low MHCp concentrations (28). Previous studies have generated conflicting results relating to the dependence of TCR down-modulation on PTK (15)(16)(17)(18)(19). Although this issues remains unclear, it does seem that PTKs play an important role in routing the endocytosed TCR for degradation in the lysosomes (13,14,17).…”

Section: Down-modulation Of Engaged and Bystander Tcrsmentioning

confidence: 99%

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Engaged and Bystander T Cell Receptors Are Down-modulated by Different Endocytotic Pathways

Monjas

Alcover

Alarcón

2004

Journal of Biological Chemistry

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T cell antigen receptor (TCR) engagement by stimulatory antibodies or its major histocompatibility complexantigen ligand results in its down-modulation from the cell surface, a phenomenon that is thought to play a role in T cell desensitization. However, TCR engagement results in the down-modulation not only of the engaged receptors but also of non-engaged bystander TCRs. We have investigated the mechanisms that mediate the down-modulation of engaged and bystander receptors and show that co-modulation of the bystander TCRs requires protein-tyrosine kinase activity and is mediated by clathrin-coated pits. In contrast, the down-modulation of engaged TCRs is independent of protein-tyrosine kinases and clathrin pits, suggesting that this process is mediated by an alternate mechanism. Indeed, down-modulation of engaged TCRs appears to depend upon lipid rafts, because cholesterol depletion with methyl-␤-cyclodextrin completely blocks this process. Thus, two independent pathways of internalization are involved in TCR down-modulation and act differentially on directly engaged and bystander receptors. Finally, we propose that although both mechanisms coexist, the predominance of one or the other mechanisms will depend on the dose of ligand.

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“…We demonstrate here that stimulation of memory CD4 T cells with a strong avidity peptide induces the highest level of apoptosis compared with stimulation with the native or weak avidity peptide, consistent with reports showing that a strong agonist can trigger death of activated T cells (45). Moreover, we found that high avidity stimulation led to extensive TCR down-regulation that likely results in reduced Ag responsiveness, as has been previously demonstrated for CTL clones (46). Conversely, low avidity stimulation is associated with a high association/dissociation kinetics (47) that may account for the maintenance of TCR expression in L115-boosted memory T cells.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Memory CD4 T Cell Function and Survival Potential by Altering the Strength of the Recall Stimulus

Patke

Farber

2005

The Journal of Immunology

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Optimization of long term immunity depends on the functional persistence of memory T cells; however, there are no defined strategies for promoting memory T cell function and survival. In this study, we hypothesized that varying the strength of the recall stimulus could modulate the function and survival potential of memory CD4 T cells. We tested the ability of peptide variants of influenza hemagglutinin (HA) exhibiting strong and weak avidity for an HA-specific TCR, to modulate HA-specific memory CD4 T cells in vitro and in vivo. In vitro stimulation with a weak avidity peptide (L115) uncoupled memory CD4 T proliferation from effector cytokine production with low apoptosis, whereas stimulation with a strong avidity peptide (Y117) fully recalled memory T cell functions but triggered increased apoptosis. To determine how differential recall would affect memory T cells in vivo, we boosted BALB/c hosts of transferred, CFSE-labeled HA-specific memory CD4 T cells with native HA, Y117, and L115 variant peptides and found differences in early Ag-driven memory T cell proliferation and IL-7R expression, with subsequent changes in memory T cell yield. High avidity boosting resulted in rapid proliferation, extensive IL-7R down-regulation, and the lowest yield of HA-specific memory cells, whereas low avidity boosting triggered low in vivo proliferation, maintenance of IL-7R expression, and the highest memory T cell yield. Our results indicate that memory CD4 T cell function and survival can be modulated at the recall level, and can be optimized by low level stimulation that minimizes apoptosis and enhances responses to survival factors.

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Transient alteration of T cell fine specificity by a strong primary stimulus correlates with T cell receptor down-regulation

Cited by 22 publications

References 56 publications

Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Engaged and Bystander T Cell Receptors Are Down-modulated by Different Endocytotic Pathways

Modulation of Memory CD4 T Cell Function and Survival Potential by Altering the Strength of the Recall Stimulus

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