Stochastic modelling of cellular immune responses: crossing the theoretical-experimental divide

The adaptive cellular immune system recognises pathogenic antigens by means of the T~cell antigen receptor (TCR), which interacts with peptide antigens displayed on the surface of antigen presenting cells (APCs) by major histocompatibility complex (MHC) proteins. The immune system contains millions of distinct TCR molecules, formed by random rearrangement of the gene segments encoding the region of the TCR molecule that interacts with the peptide-MHC (pMHC) complex. Each T~cell expresses one specific TCR species or clonotype, unique to the T~cell and the clone to which it belongs. The interaction of T~cells with APCs is a key event in the control of both self-tolerance and effector function. Understanding TCR-pMHC interactions and TCR triggering is the pre-requisite to finding suitable targets that control T~cell activation. This proposal aims to provide a systems biology approach to T~cell immunology by making use of both current mathematical and experimental models to: (1) understand T~cell receptor (TCR-CD3) triggering, TCR clustering and conformational changes at the cytoplasmic tails of the CD3 subunits, (2) understand how the T~cell repertoire structure induced by central tolerance is related to thymic self-antigen presentation statistics, and (3) understand how T~cell numbers are homeostatically regulated to maintain both the size and diversity of the T~cell repertoire. The overall goal of this proposal is to provide adaptive immunology with a quantitative and systems biology perspective. This will be achieved by making use of both current mathematical models and experimental data, in order to (i) test existing mathematical models with preliminary experimental data, (ii) refine those mathematical models, (iii) suggest new experiments and (iv) generate new experimentally testable hypothesis. Dr. Molina-Paris aims to model adaptive immune responses using stochastic methods and working closely with experimental immunologists. The proposed research project falls within the priorities and mission of BBSRC: systems biology and mathematical tools for biology. Thus, the BBSRC Research Development Fellowship is both timely to the applicant and to the BBSRC remit and UK science, in general. This Fellowship will not only open up significant new directions in the fellow's research but will also give an inter-disciplinary dimension and bring new experimental techniques and methodologies to her research, the members of her group and the members of the I2M network. Furthermore, it is also timely that this work should be carried out now as 'immunology remains crassly empirical'.

The adaptive cellular immune system recognises pathogenic antigens by means of the T~cell antigen receptor (TCR), which interacts with peptide antigens displayed on the surface of antigen presenting cells (APCs) by major histocompatibility complex (MHC) proteins. The immune system contains millions of distinct TCR molecules, formed by random rearrangement of the gene segments encoding the region of the TCR molecule that interacts with the peptide-MHC (pMHC) complex. Each T~cell expresses one specific TCR species or clonotype, unique to the T~cell and the clone to which it belongs. The interaction of T~cells with APCs is a key event in the control of both self-tolerance and effector function. Understanding TCR-pMHC interactions and TCR triggering is the pre-requisite to finding suitable targets that control T~cell activation. This proposal aims to provide a systems biology approach to T~cell immunology by making use of both current mathematical and experimental models to: (1) understand T~cell receptor (TCR-CD3) triggering, TCR clustering and conformational changes at the cytoplasmic tails of the CD3 subunits, (2) understand how the T~cell repertoire structure induced by central tolerance is related to thymic self-antigen presentation statistics, and (3) understand how T~cell numbers are homeostatically regulated to maintain both the size and diversity of the T~cell repertoire. The overall goal of this proposal is to provide adaptive immunology with a quantitative and systems biology perspective. This will be achieved by making use of both current mathematical models and experimental data, in order to (i) test existing mathematical models with preliminary experimental data, (ii) refine those mathematical models, (iii) suggest new experiments and (iv) generate new experimentally testable hypothesis.