Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion

Marchingo, Julia M.; Kan, Andrey; Sutherland, Robyn M.; Duffy, Ken R.; Wellard, Cameron; Belz, Gabrielle T.; Lew, Andrew M.; Dowling, Mark R.; Heinzel, Susanne; Hodgkin, Philip D.

doi:10.1126/science.1260044

Cited by 184 publications

(307 citation statements)

References 32 publications

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“…We found that cell populations respond to cytokine combinations in a way that is additive in nature, such that the mean response to a combination of cytokines equals the sum of the responses to the individual cytokines. Additive signal integration was observed in other studies of cellular responses (45,(54)(55)(56)(57)(58). We show that, in the case of CD4 + T-cell differentiation, however, there is a hierarchy that modulates the summation of signals: some inputs are more dominant, and if present, they modify the coefficients of the additive model.…”

Section: Discussionsupporting

confidence: 61%

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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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Section: Discussionsupporting

confidence: 61%

“…Heterogeneity in T-cell responses was shown by a number of in vitro and in vivo studies to be averaged out for a large-enough initial cell population, such that the mean population response follows more deterministic rules (38,(43)(44)(45).…”

Section: Mapping Cd4 + T-cell Differentiation Under a Large Number Ofmentioning

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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“…Accordingly, combining anti-CD40þIL2cx with IL12Fc significantly improved the quality of tumor-specific T cells with respect to many parameters. Together, our data are in line with recent work showing that T-cell division destiny depends on the integrated quality of signals 1, 2, and 3 (32). Although APC maturation is essential and usually sufficient to prevent the induction of peripheral T-cell tolerance, the immunosuppressive tumor microenvironment poses an additional challenge.…”

Section: Discussionsupporting

confidence: 89%

Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer

Bransi

Salgado

Beffinger

et al. 2015

Cancer Immunology Research

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In the context of cancer, na€ ve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 þ IL2/anti-IL2 complexes þ IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8 þ T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer.

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“…The mean division number (MDN) is calculated using the precursor cohort method as described previously. 54 For intracellular FACS staining, 3 × 10 6 cells/well were seeded in 6-well plates coated with anti-CD3 antibody as above.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

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The pro-survival proteins of the BCL-2 family regulate the survival of all cells, and genetic deletion models for these proteins have revealed which specific BCL-2 family member(s) is/are critical for the survival of particular cell types. A1 is a pro-survival BCL-2-like protein that is expressed predominantly in haematopoietic cells, and here we describe the characterisation of a novel mouse strain that lacks all three functional isoforms of A1 (A1-a, A1-b and A1-d). Surprisingly, complete loss of A1 caused only minor defects, with significant, although relatively small, decreases in γδTCR T cells, antigen-experienced conventional as well as regulatory CD4 T cells and conventional dendritic cells (cDCs). When examining these cell types in tissue culture, only cDC survival was significantly impaired by the loss of A1. Therefore, A1 appears to be a surprisingly redundant pro-survival protein in the haematopoietic system and other tissues, suggesting that its targeting in cancer may be readily tolerated. Cell Death and Differentiation (2017) 24, 534-545; doi:10.1038/cdd.2016.156; published online 13 Janaury 2017The pro-survival proteins of the BCL-2 family prevent apoptosis 1 and studies using gene-targeted mice have revealed which cell types rely on which pro-survival protein for their survival. For example, Bcl-2 −/− mice exhibit thymic and splenic atrophy, a loss of fur pigment and die~30 days post birth from polycystic kidney disease, attributable to excess lymphocyte, melanocyte and renal epithelial cell apoptosis, respectively. 2-4 Bcl-X −/− mice die before E14.5 of embryonic development because of aberrant death of erythroid and neuronal cells. 5 The generation of chimaeric or tissue-specific Bcl-X −/− revealed a critical role for BCL-XL in the survival of developing lymphocytes 5 and platelets. 6,7 Mcl-1 −/− embryos die before implantation (E3.5), 8 but conditional Mcl-1 deletion models have demonstrated an essential role for MCL-1 in the survival of haematopoietic stem cells, lymphocytes, neurons and cardiomyocytes. 9-15 Bcl-W −/− mice have impaired spermatogenesis. 16,17 A1 remains the only pro-survival BCL-2 family member for which a knockout mouse strain has not been developed. A1 was first discovered as a GM-CSF-inducible gene with significant sequence similarity to BCL-2 and MCL-1, 18 and its human homologue BFL-1 was later identified in fetal liver. 19 Overexpression of A1 protected an IL-3-dependent cell line from growth factor deprivation-induced apoptosis, thus demonstrating its pro-survival function. 20 In mice, A1 expression is restricted to the haematopoietic compartment. 18 Human BFL-1 expression is more widespread, but also predominantly haematopoietic. 21 A1 can be upregulated by NF-κB signalling, and it has been proposed that A1/BFL-1 is important for the survival of several activated immune cell subsets through stimulation of antigen or cytokine receptors. [22][23][24][25] Studies of A1 in mice are complicated by the presence of multiple isoforms that are the result of gene duplication ev...

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Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion

Cited by 184 publications

References 32 publications

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

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

Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

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Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion

Cited by 184 publications

References 32 publications

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

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

Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

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

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