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Cell-to-cell variability analysis dissects the plasticity of signaling of common ? chain cytokines in T cells.

ABSTRACT: Natural variability in the abundance of signaling regulators can lead to divergence in cell fate, even within genetically identical cells that share a common differentiation state. We introduce cell-to-cell variability analysis (CCVA), an experimental and computational methodology that quantifies the correlation between variability in signaling regulator abundance and variation in the sensitivity of cells to stimuli. With CCVA, we investigated the unexpected effects of the interleukin 2 (IL-2) receptor ? chain (IL-2R?) on the sensitivity of primary mouse T lymphocytes to cytokines that signal through receptors that have the common ? chain (?(c)). Our work showed that increased IL-2R? abundance decreased the concentration of IL-2 required for a half-maximal activation (EC(50)) of the downstream effector signal transducer and activator of transcription 5 (STAT5), but reduced the responsiveness to IL-7 or IL-15, without affecting the EC(50) values of other ?(c) cytokines. To investigate the mechanism of the effect of IL-2R? on ?(c) cytokine signaling, we introduced a Bayesian-inference computational framework that models the formation of receptor signaling complexes with data from previous biophysical measurements. With this framework, we found that a model in which IL-2R? drives ?(c) depletion through the assembly of functional IL-2R complexes was consistent with both the CCVA data and experimental measurements. The combination of CCVA and computational modeling produced quantitative understanding of the crosstalk between ?(c) cytokine receptor signaling in T lymphocytes.

SUBMITTER: Cotari JW

PROVIDER: S-EPMC3896501 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Cell-to-cell variability analysis dissects the plasticity of signaling of common γ chain cytokines in T cells.

Cotari Jesse W JW Voisinne Guillaume G Dar Orly Even OE Karabacak Volkan V Altan-Bonnet Grégoire G

Science signaling 20130312 266

Natural variability in the abundance of signaling regulators can lead to divergence in cell fate, even within genetically identical cells that share a common differentiation state. We introduce cell-to-cell variability analysis (CCVA), an experimental and computational methodology that quantifies the correlation between variability in signaling regulator abundance and variation in the sensitivity of cells to stimuli. With CCVA, we investigated the unexpected effects of the interleukin 2 (IL-2) r ...[more]

PMID: 23482665

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Project description:BackgroundSeveral members of the common gamma chain (gc) cytokine family are already approved (IL-2) or actively being developed as vaccine adjuvants and cancer immunotherapies. Studies have indicated that co-administration of gc cytokines may enhance the efficacy of immunotherapies that function via direct activation of co-stimulatory T cell receptors. To define the specific influence of gc cytokines on the co-stimulatory capacity of CD8(+) T cells and identify combinations with synergistic potential, we investigated the direct impact of gc cytokines on the differentiation and transcriptional profile of recently antigen-primed CD8(+) T cells.MethodsNaïve CD8(+) T cells were activated with peptide-pulsed APCs. After 48 hours, CD8(+) T cells were harvested and re-cultured in media supplemented with IL-2, IL-4, IL-7, IL-15 or IL-21. After 24 hours, cells were analyzed by cytokine bead array, flow cytometry, and mRNA micro-array. Gene networks responsible for specific CD8(+) T cell functions were constructed through literature-meta review and publicly available annotation databases. Gene expression data from the experimental groups was imported into this network to visualize the impact of each gc cytokine on the functional polarization of recently-activated CD8(+) T cells.ResultsAmong the gc cytokines, IL-2 induced the greatest increase in the expression of co-stimulatory receptors in recently-activated CD8(+) T cells. IL-2 increased significantly expression of 4-1BB, GITR, ICOS and OX40, at both the transcriptional and protein level. IL-2 also drove the greatest increase in cellular proliferation and the most robust shift towards a pro-survival phenotype, compared with the other gc cytokines. Both IL-4 and IL-21 enhanced expression of cytotoxic effector proteins, but drove distinct phenotypic polarizations, Th2/Tc2 and NK-like, respectively.ConclusionsOverall, these observations suggest that among gc cytokines, IL-2 may be uniquely capable of synergizing with therapeutic strategies that combine immunization with agonists of co-stimulatory T cell receptors. Previous studies have shown that the timing of IL-2 treatment relative to immunization plays a key role in defining the CD8(+) T cell response, and the findings from this study indicate that administration of exogenous IL-2 shortly after the initial antigen-priming event has concluded may augment the receptivity of these cells to subsequent TNFR co-stimulation.

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Cell-to-cell variability analysis dissects the plasticity of signaling of common ? chain cytokines in T cells.

Publications

Cell-to-cell variability analysis dissects the plasticity of signaling of common γ chain cytokines in T cells.

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