Cutting Edge: Latecomer CD8 T Cells Are Imprinted with a Unique Differentiation Program

D’Souza, Warren N.; Hedrick, Stephen M.

doi:10.4049/jimmunol.177.2.777

Cited by 115 publications

(120 citation statements)

References 30 publications

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“…Although the intermediate-primed (i.e., day 3 of the infection) T cells also developed into stable memory pool, the size of memory cells was reduced proportional to that of effectors. This is in line with a recent study in a model of vesicular stomatitis virus infection that the latecomer (i.e., day 4 of the infection) CD8 T cells were not preferentially recruited into the surviving pool of memory cells (40). In this study, we have further shown that despite differentiation into effector T cells, the late-primed (i.e., day 7 of the infection) T cells that received weakest stimulation showed lack of full cell division, survived poorly, and failed to develop into memory cells.…”

Section: Discussionsupporting

confidence: 92%

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

Quigley

Huang²,

Yang

2007

The Journal of Immunology

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Only a small fraction of effector CD8 T cells survives to become long-lived memory cells, whereas the majority of them die after an acute infection. What controls the formation of memory CD8 T cells remains mostly unknown. In this study, we showed CD8 T cells primed earlier during vaccinia viral infection received stronger stimulation, divided more extensively, and survived better than those primed later, leading to generation of a larger memory pool. Despite differentiation into effectors, the late-primed CD8 T cells lacked full cell division, displayed increased apoptosis, and failed to develop into memory cells, suggesting that the extent of stimulation influences the survival of effector CD8 T cells. We further demonstrated that the extent of stimulation, which included both the duration and the levels of antigenic stimulation/costimulation, during priming determined the formation of memory CD8 T cells via controlling the extent of Akt activation, and functional suppression of Akt led to defective CD8 memory formation in vivo. Collectively, our data suggest that the extent of stimulation controls CD8 memory formation via activation of Akt and may provide important insights into the design of effective vaccines.

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Section: Discussionsupporting

confidence: 92%

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

Quigley

Huang²,

Yang

2007

The Journal of Immunology

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“…As the response continues, the population exhibits a mixed avidity phenotype (30), suggesting that cells with lower avidity were either recruited into the response at later times or were high avidity cells that underwent active modulation of their peptide sensitivity. It was previously reported that cells that are late recruits into the anti-viral immune response can exhibit reduced proliferation and altered function (9,20,26,44). Based on this, we postulated that the lower avidity cells that we observed could result from cells that enter the LN at later times postinfection, a timepoint at which the APC/environment present in the MLN has altered such that cells with decreased peptide sensitivity can be activated.…”

Section: Lower Avidity Cells Present At Later Times Are Not the Resulsupporting

confidence: 54%

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

et al. 2013

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Numerous studies have demonstrated a critical role for T cell avidity in predicting in vivo efficacy. Even though the measurement of avidity is now a routine assessment for the analysis of effector and memory T cell populations, our understanding of how this property is controlled in vivo at both the population and individual cell levels is limited. Our previous studies have identified high avidity as a property of the initial effector population generated in mice following respiratory virus infection. As the response progresses, lower avidity cells appear in the effector pool. The studies described here investigate the mechanistic basis of this in vivo regulation of avidity. We present data supporting in vivo avidity modulation within the early high avidity responders that results in a population of lower avidity effector cells. Changes in avidity were correlated with decreased lck expression and increased sensitivity to lck inhibitors in effector cells present at late versus early times postinfection. The possibility of tuning within select individual effectors is a previously unappreciated mechanism for the control of avidity in vivo.

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“…6); however, on day 4, the reverse was true: briefly stimulated OT-I cells up-regulated IL-7R␣ and control OT-I cells down-regulated it (data not shown). At this time, it is unclear as to what is the reason for this delay in IL-7R␣ up-regulation on briefly stimulated OT-I cells (24,25). Overall, this staining pattern suggested that briefly stimulated OT-I cells were primarily developing into central memory-like CD8 T cells (26).…”

Section: Briefly Stimulated Cd8 T Cells Develop a Central Memory-likementioning

confidence: 97%

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

Usharauli

Kamala

2008

The Journal of Immunology

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It is currently believed that a brief antigenic stimulation is sufficient to induce CD8 T cells to complete their differentiation program, become effector T cells, and subsequently generate memory. Because this concept was derived from studies in which only a single effector function was analyzed (either IFN-γ production or target cell lysis), we wondered whether monitoring for multiple effector functions might reveal novel characteristics of effector CD8 T cells elicited by brief or prolonged Ag exposure. Using an in vitro system to generate effector T cells and an in vivo adoptive transfer model to track donor CD8 T cells, we found that the differentiation programs acquired by CD8 T cells after brief or prolonged antigenic stimulation were different. Although the frequencies of IFN-γ and TNF-α producers were comparable for both effector CD8 T cell populations, there were major differences in cytotoxic potential and IL-2 production. Whereas prolonged (>24 h) Ag exposure stimulated effector CD8 T cells with high cytotoxic activity and low IL-2 production, brief (<24 h) stimulation generated effector CD8 T cells with low cytotoxic activity and high IL-2 production. The latter effector T cells rapidly converted into central memory-like CD8 T cells, exhibited long-term survival in adoptively transferred hosts, and gave robust recall responses upon Ag challenge. These data suggest that not all functions of effector CD8 T cells are equally inherited after brief or prolonged antigenic stimulation.

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Cutting Edge: Latecomer CD8 T Cells Are Imprinted with a Unique Differentiation Program

Cited by 115 publications

References 30 publications

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

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Cutting Edge: Latecomer CD8 T Cells Are Imprinted with a Unique Differentiation Program

Cited by 115 publications

References 30 publications

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

Extent of Stimulation Controls the Formation of Memory CD8 T Cells

In vivoModulation of Avidity in Highly Sensitive CD8+Effector T Cells Following Viral Infection

Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production

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Product

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In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection