Proliferating CD4+ T Cells Undergo Immediate Growth Arrest upon Cessation of TCR Signaling In Vivo

Yarke, Cory A.; Dalheimer, Stacy L.; Zhang, Na; Catron, Drew M.; Jenkins, Marc K.; Mueller, Daniel L.

doi:10.4049/jimmunol.180.1.156

Cited by 23 publications

(36 citation statements)

References 45 publications

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“…The results excluded mutual T cell inhibition as a mechanism of blunted CD4 + T cell proliferation and confirmed earlier data on the issue obtained by different methods (31).…”

Section: Ag-independent Cd4 + T Cell Proliferation Is Not Affected Bysupporting

confidence: 79%

“…Two studies supplied evidence for the notion that TCRtriggered CD4 + T cells keep proliferating in the absence of Ag and cytokines (22,23), whereas others did not support such an early-programming scenario but rather supplied evidence for the importance of maintained TCR signals (24)(25)(26)(27). Most of the experiments done in vivo supported the Ag dependency of CD4 + T cells throughout the expansion phase (8,13,(28)(29)(30)(31)(32)(33).…”

Section: T Cell Receptor-mediated Recognition Of Antigenic Peptidesmentioning

confidence: 85%

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Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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“…The results excluded mutual T cell inhibition as a mechanism of blunted CD4 + T cell proliferation and confirmed earlier data on the issue obtained by different methods (31).…”

Section: Ag-independent Cd4 + T Cell Proliferation Is Not Affected Bysupporting

confidence: 79%

Section: T Cell Receptor-mediated Recognition Of Antigenic Peptidesmentioning

confidence: 85%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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“…This loss in peptide:class II molecules because of trogocytosis will be compounded for unstable peptides through the additional factor of peptide:class II dissociation. This decay in available peptide:class II will be kinetically linked to the increase in the number of T cells, driven by antigen-dependent expansion throughout the response (38,39). Thus, it is possible that competition among CD4 T cells for available peptide:MHC may explain the failure of CD4 T cells reactive to low-stability complexes to continue to expand.…”

Section: Discussionmentioning

confidence: 99%

Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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Immunodominance refers to the highly selective peptide reactivity of T cells during an immune response. In this study, we tested the hypothesis that persistence of peptide:class II complexes is one key parameter that selects the final specificity of CD4 T cells. We found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion becomes strikingly aborted in the presence of competitive T cell responses to unrelated peptides. Our experiments revealed that for inhibition to occur, the competitive responses must be initiated by the same antigen presenting cell, and it is not because of competition for MHC binding. These studies not only provide an insight into the events that regulate competitive CD4 T cell priming in vivo, but also provide a previously undescribed conceptual framework to understand the parameters that select the final specificity of the T cell repertoire during pathogen or vaccine-induced immune responses.A ntigen presenting cells (APC) ingest antigens in peripheral tissues and, in response to inflammatory signals, migrate to lymph nodes (LNs), where they present peptide antigens bound to MHC class II molecules to recirculating CD4 T cells. The majority of T cells that are primed during an immune response are selectively skewed to one or a few of the many possible peptides from an antigen, resulting in a phenomenon known as immunodominance. Our laboratory has shown that an intrinsic biochemical property of the ligand recognized by the responding T cells, the kinetic stability of the peptide:MHC class II complexes, has the major role in both predicting and determining immunodominance (1). High-stability peptides elicit dominant responses, whereas low-stability peptides do not recruit detectable responses and are thus, ''cryptic'' (1). Selectivity in the repertoire of the presented peptide:class II complexes was shown to be modulated by DM editing in APC (2-4), and to be independent of the protein context in which those peptides resided (5).Recent findings describing the dynamic interactions of antigenbearing dendritic cells (DC) and T cells suggest that peptide off-rates from class II molecules may impact the immune response (6-8). The quality of signals received through the T cell antigen receptor (TcR) by peptides of different affinity for MHC class II has recently been suggested to regulate the fate and function of CD4 T cells (9, 10). Despite new methods that allow visualization of different phases of DC:T cell interactions to antigenic stimulus in vivo (11-18), the factors that contribute to efficient T cell activation and how the kinetic features of those interactions governs the fate of the responding T cells is still unknown. The decision for a T cell to ''stop'' and form long-lived contacts with a DC when scanning for cognate antigen may depend on multiple parameters, but antigen density (12) and peptide affinity for class II (19) have been shown to augment the frequency of prolonged DC:T cell contacts, increasing the efficienc...

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“…Although differences in FE do not require recirculation, this suggests that the differences in FE occur when precursors are freed of their initial relatively stable interactions with APCs. Because CD4 T cells need continued exposure to antigen to continue their proliferation (24,25), these expanded responding cells are presumably seeking new APCs. At that time, after there has been substantial expansion in specific CD4 T cells and the amount of antigen in the system is diminishing, the number of effective APCs may be limiting even at low precursor frequencies.…”

Section: Discussionmentioning

confidence: 99%

Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number

Quiel¹,

Caucheteux²,

Laurence

et al. 2011

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

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Antigen-driven expansion of specific CD4 T cells diminishes, on a per cell basis, as infused cell number increases. There is a linear relation between log precursor number and log factor of expansion (FE), with a slope of ∼−0.5 over a range from 3 to 30,000 precursors. Cell number dependence of FE is observed at low precursor number, implying that the underlying process physiologically regulates antigen-driven T-cell expansion. FE of small numbers of transgenic precursors is not significantly affected by concomitant responses of large numbers of cells specific for different antigens. Increasing antigen amount or exogenous IL-2, IL-7, or IL-15 does not significantly affect FE, nor does FE depend on Fas, TNF-α receptor, cytotoxic T-lymphocyte antigen-4, IL-2, or IFN-γ. Small numbers of Foxp3-deficient T-cell receptor transgenic cells expand to a greater extent than do large numbers, implying that this effect is not mediated by regulatory T cells. Increasing dendritic cell number does result in larger FE, but the quantitative relation between FE and precursor number is not abrogated. Although not excluding competition for peptide/MHC complexes as an explanation, fall in FE with increasing precursor number could be explained by a negative feedback in which increasing numbers of responding cells in a cluster inhibit the expansion of cells of the same specificity within that cluster. cytokine | T-cell clusterT -cell responses to antigens are characterized by rapid expansion in numbers of specific cells, followed by a steep contraction phase and then a relative stabilization at frequencies above those in the naive cell population (1-5). We show here and others have previously reported that the factor of expansion (FE), the ratio of the number of antigen-specific cells at 7 d after immunization to the number before immunization, is dependent on the number of cells transferred (3-6). Here, we report that over a range of precursor frequencies ranging from 3 to 30,000 among lymph node T cells, there is a log-linear relation between precursor number and FE, with a slope of ∼−0.5. Estimates of the physiological frequency of antigen-specific precursors range from 20 to 3,000 per animal, corresponding to frequencies ranging from 0.2 to 30 per 100,000 naive CD4 T cells (7-10). Thus, the fall in FE described here occurs within the physiological range of precursor number and must reflect a fundamental property of antigen-mediated immune responses.

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Proliferating CD4+ T Cells Undergo Immediate Growth Arrest upon Cessation of TCR Signaling In Vivo

Cited by 23 publications

References 45 publications

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Abortive activation of CD4 T cell responses during competitive priming in vivo

Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number

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