Altan-Bonnet Research Group |
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To fight viral or bacterial infections effectively without endangering their own viability, vertebrate organisms rely on the ability of their adaptive immune system to distinguish self- from non-self agents. Among the many components of the adaptive immune system, the major CD4+ and CD8+ subsets of ab T cells recognize antigens from these infectious organisms in the form of peptides bound Major Histocompatibility Complex-encoded molecules (pMHCs). Because the intracellular machinery that generates pMHCs does not, for the most part, distinguish self-proteins from those of the invading organism, antigen-presenting cells display both foreign and self-pMHCs to the clonally distributed receptors of T cells. Thus, during an infection, the generation of a useful immune response without associated autoimmunity relies on the capacity of T cells to become activated by the non-self (pathogen-derived) pMHCs while avoiding spurious stimulation by self-derived pMHCs. 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.
Tools: combining experiments and computer models to understand T cell ligand discriminationOur previous work, combining computational modeling and experimental measurements, revealed that ligand discrimination by T cells is controlled by the dynamics of two competing feedback loops in the signaling response activated by TCR engagement. These signaling feedback loops control a high gain digital amplifier that sets a threshold in terms of the quality of ligand-receptor interaction effective in activating the T cell. Together with the filtering effect of thymic selection on the self-specific repertoire, this contributes to useful self/non-self discrimination.
One of the main predictions from our work is that the threshold for such discrimination could be modulated during differentiation by modest alterations in the intracellular concentration of key signaling proteins, an effect that could have important implications for a positive role of self-recognition in anti-foreign immune responses. The same considerations raised the issue of whether stochastic fluctuations in the levels of expression of key signaling components in naïve T cells or the progeny of clonally expanded precursors could introduce errors in ligand discrimination that foster autoimmune responses.
Project: probing the robustness and adaptability of T cell ligand discriminationOur working hypothesis is that the TCR signaling machinery sets a threshold for functional discrimination among pMHC (i.e. TCR ligands) by adjusting the relative efficacies of competing feedback regulatory pathways. The paradox we aim to solve is that T cells display both robustness and adaptability in ligand discrimination. Modulation of the agonist-nonagonist discrimination threshold is modulated during cellular differentiation, yet, within a given stage of differentiation, the signaling network of the T cell maintains a consistent (robust) threshold despite fluctuations in the concentrations of individual components.
Our general approach consists of combining experimental measurements of ligand discrimination by T cells at different stages of differentiation (from immature thymocytes in the thymus, to mature naïve and memory-like lymphocytes in the periphery) with computer simulations of T cell signaling, in order to test how ligand discrimination is reliably defined and tuned by T cells in the adaptive immune system. Our ultimate goal is to provide such a quantitative understanding of self/non-self discrimination by T lymphocytes in the immune system, in order to allow controlled modulation in clinical applications (e.g. targeted cytotoxicity against self-derived antigens on the surface of tumor cells).
