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.
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.
|Malandro, Nicole; Budhu, Sadna; Kuhn, Nicholas F et al. (2016) Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion. Immunity 44:179-93|
|Chen, Ying-Han; Du, WenLi; Hagemeijer, Marne C et al. (2015) Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160:619-30|
|Voisinne, Guillaume; Nixon, Briana G; Melbinger, Anna et al. (2015) T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens. Cell Rep 11:1208-19|
|Prill, Robert J; Vogel, Robert; Cecchi, Guillermo A et al. (2015) Noise-driven causal inference in biomolecular networks. PLoS One 10:e0125777|
|Tkach, Karen E; Oyler, Jennifer E; Altan-Bonnet, GrÃ©goire (2014) Cracking the NF-ÎºB code. Sci Signal 7:pe5|
|Tkach, Karen E; Barik, Debashis; Voisinne, Guillaume et al. (2014) T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks. Elife 3:e01944|
|Cotari, Jesse W; Voisinne, Guillaume; Altan-Bonnet, GrÃ©goire (2013) Diversity training for signal transduction: leveraging cell-to-cell variability to dissect cellular signaling, differentiation and death. Curr Opin Biotechnol 24:760-6|
|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 Î³ chain cytokines in T cells. Sci Signal 6:ra17|
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