Our long-term goal is to probe theoretically and experimentally how reliable immune responses emerge at the system level from the unreliable responses of individual T cells. Our first project aims at probing how heterogeneity in the expression levels of key signaling proteins generates phenotypic variability in T cells'responsiveness to ligands. We will also probe how such stochasticity of signaling responses translates into functional phenotypic variability.
Our second aim tests how multiplexed signals (e.g. T cell ligands and IL15 cytokine) can activate signaling crosstalks that modulate the levels and/or activity of key signaling proteins and make T cells hyperresponsive to self-derived ligands.
Our third aim probes how cytokine regulation integrates cell variability in antigen response at the individual cell level towards a regulated collective response. This project focuses on Interleukin-2 as a critical cytokine that controls quorum sensing among effector T cells and suppression by regulatory T cells. Our approach is fundamentally interdisciplinary with concomitant computational modeling and experimental testing. It consists in making and validating theoretical predictions to quantify and control how immune responses emerge as dynamically- and collectively-regulated properties of individual T cells.

Public Health Relevance

Our project focuses on developing experimentally-validated computer models of T cell activation. Our goal is to identify how reliable immune responses emerge dynamically from the unreliable activation of individual T cells. The long-term impact of our research is in a better control of immune responses towards immunotherapies for cancer and auto- immune disorders.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Gondre-Lewis, Timothy A
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Tkach, Karen E; Oyler, Jennifer E; Altan-Bonnet, Grégoire (2014) Cracking the NF-?B code. Sci Signal 7:pe5
Tkach, Karen; Altan-Bonnet, Gregoire (2013) T cell responses to antigen: hasty proposals resolved through long engagements. Curr Opin Immunol 25:120-5
Francois, Paul; Voisinne, Guillaume; Siggia, Eric D et al. (2013) Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism. Proc Natl Acad Sci U S A 110:E888-97
Cotari, Jesse W; Voisinne, Guillaume; Dar, Orly Even et al. (2013) Cell-to-cell variability analysis dissects the plasticity of signaling of common ? chain cytokines in T cells. Sci Signal 6:ra17
Cotari, Jesse W; Voisinne, Guillaume; Altan-Bonnet, Gregoire (2013) Diversity training for signal transduction: leveraging cell-to-cell variability to dissect cellular signaling, differentiation and death. Curr Opin Biotechnol 24:760-6
Gottschalk, Rachel A; Hathorn, Matthew M; Beuneu, Helene et al. (2012) Distinct influences of peptide-MHC quality and quantity on in vivo T-cell responses. Proc Natl Acad Sci U S A 109:881-6
Romano, Emanuela; Cotari, Jesse W; Barreira da Silva, Rosa et al. (2012) Human Langerhans cells use an IL-15R-*/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. Blood 119:5182-90
Quann, Emily J; Liu, Xin; Altan-Bonnet, Gregoire et al. (2011) A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. Nat Immunol 12:647-54
Coward, Jesse; Germain, Ronald N; Altan-Bonnet, Grégoire (2010) Perspectives for computer modeling in the study of T cell activation. Cold Spring Harb Perspect Biol 2:a005538
Prill, Robert J; Marbach, Daniel; Saez-Rodriguez, Julio et al. (2010) Towards a rigorous assessment of systems biology models: the DREAM3 challenges. PLoS One 5:e9202

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