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 and in autoimmune diseases. The effector functions of T cells are mediated largely by proteins termed cytokines that either be expressed at the cell surface or secreted. T cells see 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. A central issue is the relationship between the amount of signaling received by the cell from receptors seeing peptide-MHC ligand and the functional response of each T cell. Another major concern is the extent to which different cells, even with identical receptors, show different biological response patterns. We have used new methods for analyzing T cell recognition events and cytokine production by individual cells to address these issues. We previously showed that both T cells exhibit a hierarchical organization of response thresholds - in other words, more antigen is needed to elicit one particular response as compared to another from the same T cell. Therefore, as antigen concentration changes, so does the mix of effector molecules produced by the cells. This alters the quality as well as the quantity of an immune response as the amount of antigen changes in a host. Our prior studies also revealed cell-to-cell heterogeneity in the responses of T cells with identical antigen receptors. We have extended our studies of this phenomenon to demonstrate that individual cells show marked variation in cytokine production profile upon antigen stimulation, even though the population maintains a uniform distribution of these responses upon multiple rounds of stimulation and expansion. These data have important implications for understanding the dynamics of immune responses in vivo that may involve cells of identical antigen specificity showing distinct effector activities. We have also analyzed the relationship between TCR recognition of peptide:MHC ligands and these functional responses by also examining receptor downmodulation. We confirmed the results of Lanzavecchia concerning ?serial engagement? of TCR and showed that the extent of such serial triggering reflects of the receptor-associated signaling events evoked by ligands of various quality. These latter support our previously proposed hierarchical model and begin to provide a mechanistic basis for this property of T- lymphocytes. - Cytokines; Th1 cells, Th2 cells; TCR signaling; cell heterogeneity.
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