Nature versus nurture in T cell cytokine production

FitzPatrick, David R.; Kelso, Anne

doi:10.1002/jlb.66.6.869

Cited by 10 publications

(10 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously used a theoretical approach to evaluate whether Th1 and Th2 cytokines instruct the differentiation of uncommitted cells into Th1 or Th2 cells, respectively, or if they select the growth of Th1 and Th2 cells that have been committed through a stochastic process 7 . Our model predicted that both types of mechanisms are likely to be involved, consistent with a number of experiments supporting both mechanisms 8 , 9 , 10 . In the present study, we extend this modelling approach to investigate the selective regulatory mechanisms in detail by including cytokines that are allowed to diffuse and interact with receptors on individual Th cells.…”

supporting

confidence: 73%

“…7 Our model predicted that both types of mechanisms are likely to be involved, consistent with a number of experiments supporting both mechanisms. [8][9][10] In the present study, we extend this modelling approach to investigate the selective regulatory mechanisms in detail by including cytokines that are allowed to diffuse and interact with receptors on individual Th cells.…”

mentioning

confidence: 99%

“…12 Most data support the concept that both cytokines can act during the differentiation process, so that IL-12 and IL-4 promote differentiation of the uncommitted Th cell into Th1 or Th2, respectively, and/or act as growth factors by selectively expanding already differentiated Th1 or Th2 cells. [8][9][10] The process for Th1 cells is complex, as it involves a positive feedback loop in which the IFN-g molecules, secreted by Th1 cells, stimulate the production of IL-12 by macrophages, which then promotes further Th1 development. [11][12][13] By contrast, Th2 cells rely on a simple autocrine system in which they may capture and react to their own secreted IL-4 molecules.…”

mentioning

confidence: 99%

See 2 more Smart Citations

3D computation modelling of the influence of cytokine secretion on Th‐cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL‐4 for Th2 cell dominance

et al. 2007

View full text Add to dashboard Cite

Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-c (IFN-c) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor-ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 lm and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

show abstract

supporting

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

3D computation modelling of the influence of cytokine secretion on Th‐cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL‐4 for Th2 cell dominance

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The probability of each cell to express a gene in such a system seems to be set by both, intrinsic (basal probability, e.g., loci accessibility for different differentiation states) and extrinsic factors (dynamic probability e.g., strength of extracellular signals) (28).…”

Section: Tcr Signal Strength Modulates the Probability Of Il-10 Transmentioning

confidence: 99%

Stochastic Monoallelic Expression of IL-10 in T Cells

Calado

Paixão

Holmberg

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

IL-10 is a potent anti-inflammatory and immunomodulatory cytokine, exerting major effects in the degree and quality of the immune response. Using a newly generated IL-10 reporter mouse model, which easily allows the study of IL-10 expression from each allele in a single cell, we report here for the first time that IL-10 is predominantly monoallelic expressed in CD4+ T cells. Furthermore, we have compelling evidence that this expression pattern is not due to parental imprinting, allelic exclusion, or strong allelic bias. Instead, our results support a stochastic regulation mechanism, in which the probability to initiate allelic transcription depends on the strength of TCR signaling and subsequent capacity to overcome restrictions imposed by chromatin hypoacetylation. In vivo Ag-experienced T cells show a higher basal probability to transcribe IL-10 when compared with naive cells, yet still show mostly monoallelic IL-10 expression. Finally, statistical analysis on allelic expression data shows transcriptional independence between both alleles. We conclude that CD4+ T cells have a low probability for IL-10 allelic activation resulting in a predominantly monoallelic expression pattern, and that IL-10 expression appears to be stochastically regulated by controlling the frequency of expressing cells, rather than absolute protein levels per cell.

show abstract

“…5a). Production of IFN-γ represents activation of memory T cells ( 21 ). It can be seen that splenocytes from mice transplanted with syngeneic hearts did not show IFN-γ responses to B10.A hearts from Hsp-27tg or LC mice.…”

Section: Resultsmentioning

confidence: 99%