Computational biologist Grégoire Altan-Bonnet focuses on probing and testing the integration of cellular activation that makes up the immune response.
Altan-Bonnet Lab @ cBio
Visit the Altan-Bonnet lab's Web site at cBio.org
Vertebrate organisms rely on the ability of their adaptive immune system to distinguish self- from non-self agents, to fight efficiently viral or bacterial infections without endangering their own viability. This discrimination between self and non-self agents is fundamental: in the immune system, antigen-presenting cells (APC) constantly process proteins to present on their surface as peptide Major Histocompatibility Complex (pMHC). During an infection, pMHCs' derived from the pathogen are presented by APC to T cells: the immune response relies on the specific activation of T cells upon detecting these non-self (pathogen-derived) pMHCs'. However, spurious activation of T cells by self-derived pMHC must be avoided to prevent auto-immune responses. A major contribution to this pMHC discrimination is the elimination during thymic development of many immature T cells possessing T cell receptors (TCRs') that are highly reactive with self pMHCs. However, this cellular selection itself depends on the capacity of the TCR to make fine distinctions between closely related pMHC structures when transducing signals that regulate cell survival and differentiation, distinctions that also must be made by mature, post-thymic T cells. Hence, at different stages of their lifespan, T cells endowed with a given TCR must be able to perform reliable yet flexible pMHC discrimination.
By combining computational modeling and experimental measurements, we are testing how ligand discrimination by T cells is controlled by the dynamics of their signaling response. We have shown how two competing feedback loops control a high gain digital amplifier which sets a threshold in terms of the quality of ligand-receptor interaction and defines self/non-self discrimination. We are currently focusing on issues of robustness and adaptability in T cell ligand discrimination. The threshold of self/non-self discrimination can be modulated during differentiation by simple alterations in the intracellular concentrations of key signaling proteins: there is adaptability in ligand discrimination. On the other hand, the heterogeneity of T cells in terms of the levels of expression of key signaling components or differences in the TCR structure could potentially introduce a dangerous unreliability in ligand discrimination, leading to auto-immune disorders: there must be robustness in T cell ligand discrimination.
Our research goal is to reconcile the robustness and adaptability of T cell ligand discrimination, through a combination of experimental and computational approaches. Understanding better T cell ligand discrimination will open up theoretical avenues to manipulate T cell responsiveness, towards immunotherapeutic applications.
Cotari JW, Voisinne G, Dar OE, Karabacak V, Altan-Bonnet G. Cell-to-cell variability analysis dissects the plasticity of signaling of common γ chain cytokines in T cells. Sci Signal. 2013 Mar 12;6(266):ra17. doi: 10.1126/scisignal.2003240.
François P, Voisinne G, Siggia ED, Altan-Bonnet G, Vergassola M. Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):E888-97. doi: 10.1073/pnas.1300752110. Epub 2013 Feb 19.
Feinerman O, Jentsch G, Tkach KE, Coward JW, Hathorn MM, Sneddon MW, Emonet T, Smith KA, Altan-Bonnet G. Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response. Mol Syst Biol. 2010 Nov 30;6:437. doi: 10.1038/msb.2010.90.
Feinerman O, Veiga J, Dorfman JR, Germain RN, Altan-Bonnet G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science. 2008 Aug 22;321(5892):1081-4. doi: 10.1126/science.1158013.
Tkach KE, Barik D, Voisinne G, Malandro N, Hathorn MM, Cotari JW, Vogel R, Merghoub T, Wolchok J, Krichevsky O, Altan-Bonnet G. Elife (Cambridge). 2014 Apr 9;3:e01944. doi: 10.7554/eLife.01944.
Altan-Bonnet G, Germain RN. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 2005 Nov;3(11):e356. Epub 2005 Oct 25.
Development of methods to analyze cell-to-cell variability within isogenic population of cells
Quantitative analysis of the role of cytokine competition as a key mediator of the balance between tolerance and response among T lymphocytes
Development of a fully integrated computational/experimental approach to study the immune response