Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations

Kelso, Anne; Groves, Penny; Ramm, Louise E.; Doyle, Anthony

doi:10.1093/intimm/11.4.617

Cited by 59 publications

(44 citation statements)

References 28 publications

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“…The lack of association of expression among IL-4, IL-5, and IL-10 has been recently reported by Kelso et al 22, who analyzed the single-cell expression patterns in type 1– or type 2–polarized responses.…”

Section: Discussionmentioning

confidence: 82%

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Moulin

Andris

Thielemans

et al. 2000

The Journal of Experimental Medicine

234

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Increasing evidence indicates that dendritic cells (DCs) are the antigen-presenting cells of the primary immune response. However, several reports suggest that B lymphocytes could be required for optimal T cell sensitization. We compared the immune responses of wild-type and B cell-deficient (μMT) mice, induced by antigen emulsified in adjuvant or pulsed on splenic dendritic cells. Our data show that lymph node cells from both control and μMT animals were primed, but each released distinct cytokine profiles. Lymph node T cells from control animals secreted interferon (IFN)-γ, interleukin (IL)-2, and IL-4, whereas those from μMT mice produced IFN-γ and IL-2 but no IL-4. To test whether B cells may influence the T helper cell type 1 (Th1)/Th2 balance by affecting the function of DCs, we immunized mice by transferring antigen-pulsed DCs from wild-type or mutant mice. Injection of control DCs induced the secretion of IL-4, IFN-γ, and IL-2, whereas administration of DCs from μMT animals failed to sensitize cells to produce IL-4. Analysis of IL-12 production revealed that DCs from μMT mice produce higher levels of IL-12p70 than do DCs from wild-type animals. These data suggest that B lymphocytes regulate the capacity of DCs to promote IL-4 secretion, possibly by downregulating their secretion of IL-12, thereby favoring the induction of a nonpolarized immune response.

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Section: Discussionmentioning

confidence: 82%

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Moulin

Andris

Thielemans

et al. 2000

The Journal of Experimental Medicine

234

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“…However, this notion is challenged by evidence of population heterogeneity (29)(30)(31)(32) and Th cell plasticity (33)(34)(35)(36)(37), showing that, under various conditions, differentiated cells can adopt hybrid phenotypes, coexpressing signature TFs and cytokines of different lineages. We and others have recently shown that naïve CD4 + T cells can differentiate into a mixed Th1-Th2 phenotype, coexpressing lineage-specific TFs and cytokines of both cell types in varying levels depending on the relative levels of input cytokine signals (38)(39)(40).…”

Section: Significancementioning

confidence: 99%

Diverse continuum of CD4⁺T-cell states is determined by hierarchical additive integration of cytokine signals

Eizenberg-Magar

Rimer

Zaretsky

et al. 2017

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

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During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, we systematically mapped the response of CD4 + T cells to a large number of input cytokine combinations that drive their differentiation. We find that, in response to varied input combinations, cells differentiate into a continuum of cell fates as opposed to a limited number of discrete phenotypes. Input cytokines hierarchically influence the cell population, with TGFβ being most dominant followed by IL-6 and IL-4. Mathematical modeling explains these results using additive signal integration within hierarchical groups of input cytokine combinations and correctly predicts cell population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using a segmented linear approach, providing a framework for prediction of cellular responses to new cytokine combinations and doses, with implications to fine-tuned immunotherapies.C ell differentiation is controlled by complex gene regulatory networks that determine the expression of a large number of genes in response to external stimuli. CD4 + T cells, central regulators of immune responses, can differentiate into a number of phenotypes (or cell states), each defined by the expression of a panel of genes, such as lineage-specifying transcription factors (TFs) and cytokines (1). Differentiation outcome depends on a number of factors, including strength of antigen stimulation (2, 3), interactions with antigen presenting cells, and the signaling environment defined by secreted cytokines (1). By applying specific cytokine signals, it is possible to direct antigen-activated T cells toward differentiation into a number of specific phenotypes. Although the molecular interactions and regulatory networks that govern the differentiation process are being revealed at increasing resolution (4, 5), understanding the logic of operation of these complex networks and developing predictive mathematical models for cellular responses remain a challenge.Mathematical models that describe complex cellular processes are difficult to construct because of a lack of complete information about the underlying networks of molecular interactions and in particular, missing quantitative data regarding the parameters of biochemical interactions within these networks. Alternatively, a "black box" approach can be used, constructing a model of the system by analyzing its response to different input conditions (Fig. 1A). This technique enables study of complex systems in a simplified manner, because its implementation merely requires measurable inputs and outputs, without quantifying the response of each component inside the box. Approaches based on this concept are highly useful for describing engineered systems and were also applied for studying som...

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“…The diversity of cytokine expression patterns seen in polyclonal T cell populations and T cell clones has been shown to exceed the type 1 and type 2 patterns [3][4][5][6]. Incontrovertible studies have detected simultaneous expression of multiple type 1 and type 2 cytokine mRNAs or proteins in single T cells [7][8][9][10][11]. New categories such as Th3 or Tr1 [12,13] have been proposed to accommo-date a few of these unconventional patterns.…”

Section: Patterns Of Differential T Cell Cytokine Productionmentioning

confidence: 99%

Nature versus nurture in T cell cytokine production

FitzPatrick

Kelso

1999

Journal of Leukocyte Biology

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Both extrinsic and intrinsic factors influence the development of cytokine expression patterns in T lymphocytes. The models proposed to accommodate these factors are often separated into two types: deterministic (or instructional) and probabilistic (or stochastic). In this review we compare these two types of models and examine how they account for different stages of T cell cytokine responses to antigen stimulation.

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Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations

Cited by 59 publications

References 28 publications

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Diverse continuum of CD4⁺T-cell states is determined by hierarchical additive integration of cytokine signals

Nature versus nurture in T cell cytokine production

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Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations

Cited by 59 publications

References 28 publications

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Diverse continuum of CD4+T-cell states is determined by hierarchical additive integration of cytokine signals

Nature versus nurture in T cell cytokine production

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Diverse continuum of CD4⁺T-cell states is determined by hierarchical additive integration of cytokine signals