T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks
| Autor: | Matthew M Hathorn, Taha Merghoub, Nicole Malandro, Karen E Tkach, Oleg Krichevsky, Robert Vogel, Jesse W. Cotari, Guillaume Voisinne, Grégoire Altan-Bonnet, Debashis Barik, Jedd D. Wolchok |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_treatment
Melanoma Experimental Cell Communication Lymphocyte Activation T-Lymphocyte Subsets STAT5 Transcription Factor cytokine Phosphorylation Biology (General) Cells Cultured Feedback Physiological Genetics Systems immunology General Neuroscience General Medicine Biophysics and Structural Biology Phenotype Cytokine medicine.anatomical_structure Medicine Signal transduction Research Article Signal Transduction medicine.drug Interleukin 2 Cell signaling immune monitoring Genotype QH301-705.5 feedback regulation Science T cell Immunology Receptors Antigen T-Cell Mice Transgenic systems immunology Biology T lymphocyte activation General Biochemistry Genetics and Molecular Biology Paracrine signalling Lymphocytes Tumor-Infiltrating Antigen Antigens Neoplasm medicine Animals Computer Simulation Antigens mouse General Immunology and Microbiology Models Immunological self-organization Coculture Techniques Mice Inbred C57BL Kinetics Nonlinear Dynamics Interleukin-2 Neuroscience |
| Zdroj: | eLife, Vol 3 (2014) eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.01944 |
| Popis: | Variability within isogenic T cell populations yields heterogeneous ‘local’ signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global’ antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring. DOI: http://dx.doi.org/10.7554/eLife.01944.001 eLife digest The cells of the immune system face the challenge of removing viruses and other pathogens without endangering healthy tissues. Cells called T cells plays a variety of roles in the immune response: some T cells directly destroy infected cells, some recruit other cells called phagocytes to the site of infection, and some release small proteins called cytokines. These cytokines help cells to communicate with other cells and, therefore, to tailor the overall immune responses to deal with a particular pathogen. It is known that mammals are capable of adjusting the T cell response to match the overall severity of an infection. However, it is not clear how individual T cells coordinate their seemingly binary response—they are either activated when they recognize a pathogen, or they are not activated—into a response at the collective cell level that can be varied continuously over a wide range of values. Here, Tkach et al. show that T cell populations match their production of the cytokine interleukin 2 (IL-2) to the abundance of antigens—molecules released by the pathogen—over an unexpectedly large range of concentrations. Through a combination of experimental and computational analyses, Tkach et al. identified two novel IL-2 feedback loops that help to generate the correct quantity of cytokine, irrespective of the total number of T cells. Furthermore, this model can be used to estimate antigen quantities within diseased tissues. The work of Tkach et al. illustrates the potential of feedback integration in cell signalling and gene regulation as a mechanism to allow cellular populations to respond to environmental stimuli in a graded, collective fashion. DOI: http://dx.doi.org/10.7554/eLife.01944.002 |
| Databáze: | OpenAIRE |
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