Analysis Of T Cell Receptor Structure And Function

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Abstract

White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies/asthma due to the development of an unwanted or excessive type of immune response to substances (antigens) in our environment and in autoimmune diseases. Because T cells respond to foreign substances (antigens) in the form of peptide- major histocompatibility complex (MHC) molecule complexes on cell surfaces, we wish to know how such complexes interact with specific receptors to evoke the effector activities of mature T cells in the body, as well as regulate their growth, inactivation, or death. In particular, we want to understand in molecular detail the protein-protein interactions that turn recognition of antigen by T cells into signals guiding the normal survival and effector functions of these cells, how variations in these recognition and signaling events leads to desirable versus undesirable forms of immunity, and how we can manipulate these events to augment useful immune responses and inhibit damaging ones. Our studies currently focus on new biochemical regulatory pathways that help T-cells discriminate between self- and foreign peptide:MHC molecule complexes, on the role of self-recognition in the sensitivity of T-cells to antigen on presenting cells of the types studied in LI545, and on the explicit mathematical modeling of these and other signaling processes in eukaryotic cells. During the past year we have reported our analysis of the molecular details of two novel regulatory pathways controlling early signaling by the T-cell receptor (SHP-1 phosphatase dependent negative control and MAPK mediated positive control). Our current work involves the creation of a full mathematical / computer description of T cell receptor (TCR) signaling that incorporates these novel regulatory pathways. Preliminary results from this modeling suggest that these feedback controls play a crucial role in creating a sharp transition from non-agonist to agonist behavior for ligands with varying affinities for the receptor. Our microscopy studies demonstrated the polarization of TCR among naive T cells in vivo that is induced / maintained by self-MHC recognition. Our studies of cytoskeletal adapter proteins (ERM molecules) have revealed the regulation of T-cell cytoskeletal rigidity by TCR signals and the role of small GTPases (Rac, CDC42) in this regulatory process. We have extended our studies showing that recently activated T cells acquire overt reactivity to self-antigens, which we believe helps expand clonal precursors during the period of antigen limitation early in an infectious process. Finally, we have modified or developed new computer programs that allow simulation in space and time of the behavior of cells in chemokine gradients and of receptors and signaling molecules on and below the cell membrane. The chemotaxis model has been able to predict a number of features of cellular responses to chemoattractants that were not previously appreciated, suggesting that the model is robust and capable of helping to shape future biological experimentation in an insightful manner. We are currently attempting to use this model to predict the chemotactic behavior of lymphocytes and to relate this in silico work to real world studies of T lymphocyte migration and protein molecule redistribution prior to T cell contact with an antigen-presenting cell that is the source of the attracting chemokine.