Computational biologist Grégoire Altan-Bonnet focuses on probing and testing the integration of cellular activation that makes up the immune response.
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.