Increasing the CD4+ T Cell Precursor Frequency Leads to Competition for IFN-γ Thereby Degrading Memory Cell Quantity and Quality

Whitmire, Jason K.; Benning, Nicola; Eam, Boreth; Whitton, J. Lindsay

doi:10.4049/jimmunol.180.10.6777

Cited by 29 publications

(34 citation statements)

References 68 publications

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“…77 Competition during the primary CD4 + T-cell response for factors other than TCR, such as IFNc, has also been shown to impact the quantity and quality of ensuing memory T-cell populations. 78 Our recent findings have also indicated that not all CD4 + T-cell clones that undergo massive expansion and effector differentiation in response to acute infection are capable of populating the memory pool. 79 Small numbers of adoptively transferred SMARTA TCR transgenic T cells, which are specific for the lymphocytic choriomeningitis virus (LCMV) glycoprotein-derived immunodominant CD4 + T-cell epitope GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] , effectively mimic endogenous CD4 + T-cell responses in the same host following LCMV infection.…”

Section: Tcr-driven Differentiation: Cd4 + T Cellsmentioning

confidence: 95%

Nature and nurture: T‐cell receptor‐dependent and T‐cell receptor‐independent differentiation cues in the selection of the memory T‐cell pool

Kim

Williams

2010

Immunology

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SummaryThe initiation of a T-cell response begins with the interaction of an individual T-cell clone with its cognate antigen presented by MHC. Although the strength of the T-cell receptor (TCR) -antigen-MHC (TCR-pMHC) interaction plays an important and obvious role in the recruitment of T cells into the immune response, evidence in recent years has suggested that the strength of this initial interaction can influence various other aspects of the fate of an individual T-cell clone and its daughter cells. In this review, we will describe differences in the way CD4 + and CD8 + T cells incorporate antigen-driven differentiation and survival signals during the response to acute infection. Furthermore, we will discuss increasing evidence that the quality and/or quantity of the initial TCR-pMHC interaction can drive the differentiation and long-term survival of T helper type 1 memory populations.

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Section: Tcr-driven Differentiation: Cd4 + T Cellsmentioning

confidence: 95%

Nature and nurture: T‐cell receptor‐dependent and T‐cell receptor‐independent differentiation cues in the selection of the memory T‐cell pool

Kim

Williams

2010

Immunology

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“…Among possible mechanisms determining the poorer expansion seen at higher precursor frequency would be competition of the responding cells for access to peptide/MHC complexes and/ or for costimulatory molecules expressed on the APC (11,26,27), competition for locally produced growth-promoting factors (28)(29)(30), or inhibition by the action of cells within the microenvironment of the cluster of responding cells (11).…”

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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“…as they respond to infection (30, 31). We hypothesized that the LAG-3 −/− P14 cells better competed for these resources than WT P14 cells and were better able to accumulate after infection.…”

Section: Resultsmentioning

confidence: 99%

LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses

Cook

Whitmire

2016

The Journal of Immunology

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Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8+ T cells during chronic virus infection and anti-tumor responses. However, the T cell response in LAG-3 deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8+ T cell responses. Our results indicate that LAG-3 expression by CD8+ T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison to LAG-3 deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8+ T cell responses.

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Increasing the CD4+ T Cell Precursor Frequency Leads to Competition for IFN-γ Thereby Degrading Memory Cell Quantity and Quality

Cited by 29 publications

References 68 publications

Nature and nurture: T‐cell receptor‐dependent and T‐cell receptor‐independent differentiation cues in the selection of the memory T‐cell pool

Nature and nurture: T‐cell receptor‐dependent and T‐cell receptor‐independent differentiation cues in the selection of the memory T‐cell pool

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

LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses

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