T cell transcriptomes : uncovering the mechanisms for T cell effector function through gene profiling

T cells are at the heart of the adaptive immune response. They mediate many important immunological processes that provide protection against viruses, bacteria and other pathogens. The aim of the work described in this thesis was to use gene expression profiling to gain insights into different aspects of T cell biology. In particular we wanted to examine the mechanisms and identify the genes that underlie T cell effector function. IFN-g-producing Th1 cells are a major effector subset that protects against intracellular pathogens, while Th2 cells produce IL-4, IL-5 and IL-13 and mediate protection against large extracellular pathogens. Microarray profiling of gene expression in mouse and human Th1 and Th2 cells, as well as mouse Tc1 and Tc2 cells, identified a number of novel markers of these T cells which may have important roles in T cell differentiation/function. We found that T cell type, host species and differentiation conditions significantly influenced gene expression profiles generated during T cell polarization.Providing help to B cells for antibody production is the major function of the third effector subset of CD4+ T cells termed T follicular homing or TFH cells. Relatively little is known about the generation of these cells, and the mechanisms of their effector function. Using oligonucleotide microarrays we identified a TFH-specific gene expression signature, which included many novel genes which will undoubtedly enable better identification and characterization of this novel subset. A comprehensive study profiling all the major leukocyte subsets revealed their distinct gene expression signatures and numerous leukocyte subset specific genes. A detailed examination of most major T cell subsets identified distinguishing features of each subset together with gene expression changes associated with T cell activation and exposure to cell culture conditions. In addition, we described a distinctive transcriptional profile for gd T cells and examined the differences between central and effector memory T cells. We also showed that specific gene expression signatures provide a powerful tool for subset classification. Taken together this work provides important insights into T cell differentiation and effector function, and presents a basis for future work examining numerous novel genes relevant to T cell biology