Regulation of Effector and Memory T Cell Differentiation by Transcription Factor FoxO1 and I[kappa]B[alpha] Nuclear Export of NF-[kappa]B PDF Download

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Although in CD8 T cells, NF-kappa-B family members, are known to play a role in T cell activation, proliferation and activation, effector function, and differentiation, it remains unclear whether the dependence on I-kappa-B-alpha for export of NF-kappa-B proteins plays a role in, effector and/or memory CD8 T cell differentiation, and maintenance of memory CD8 T cells during an acute infection. Dr. Miyamoto has developed the NfkbiaNES/NES mice, in which the nuclear export sequence of I-kappa-B-alpha is mutated, and thus NF-kappa-B export from the cell nucleus to the cytoplasm does not occur. Using these mice, in chapter five, I investigated the physiological significance of I-kappa-B-alpha nuclear export in CD8 T cell differentiation during an acute LCMV infection. Strikingly, we found that the NES mutation of I-kappa-B-alpha greatly diminishes CD8 T cell activation, differentiation, and IFN-gamma production among virus-specific effector CD8 T cells. We also found that it regulates CD8 T cell memory differentiation by the reduction of key transcription factors such as FoxO1 and TCF-1. Together, these findings have provided fundamental insights into the role of I-kappa-B-alpha nuclear export of NF-kappa-B and its regulation of the homeostasis of CD8 T cell memory to intracellular pathogens. CD4 T cells, otherwise known as "T helper cells" are mainly recognized for their ability to help B cell and CD8 T cell responses. Current research has elucidated many different CD4 T cell lineages, their memory differentiation, and additional roles for these CD4 T cells in immunity to viruses. Unlike the field of memory CD8 T cells, the field of memory CD4 T cells must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. To date there are at least seven distinct CD4 T cell effector lineages: TH1, TH2, TH17, TFH TREG, TH22, and TH9. Parallel to the effector CD8 T cell population, effector CD4 T cell lineage commitment is established early in response to infection, which is followed by their differentiation into a heterogeneous population of effector CD4 T cells that can then acquire unique characteristics that endow them with the ability to become a stable pool of memory CD4 T cells. Their cell fate is influenced by signaling during priming as well as by signals acquired during the effector stage and clearance of the infection. Thus, the nature and combination of the cytokine signaling in the local environmental milieu of activated CD4 T cells influences their proliferative potential, effector differentiation, and memory capacities. Further, the balance of these signals, otherwise known as "polarizing conditions", helps drive CD4 T cell lineage commitment by inducing lineage-defining cytokines and their respective transcription factors. Hence, the mechanisms that regulate the number and quality of memory CD4 T cells is very poorly understood. In chapter six, I elucidate a novel role of I-kappa-B-alpha nuclear export of NF-kappa-B in CD4 T cell differentiation during an acute LCMV infection. In this study, we report that nuclear export of I-kappa-B-alpha plays an integral role in the differentiation of TH1 and TFH CD4 T cell memory subsets by regulating the balance of key transcription factors T-bet, Bcl-6 and Blimp-1. We also find that the NES mutation in I-kappa-B-alpha dysregulates the antigen-induced production of IFN-gamma by virus-specific CD4 T cell. Hence, we propose that nuclear export of I-kappa-B-alpha is a key regulator that steers TH1 and TFH CD4 T cell memory differentiation. These findings have provided fundamental insights into the mechanisms that regulate CD4 T cell differentiation and viral clearance. In conclusion, my studies have elucidated and advanced our understanding for the molecular requirements of both FoxO1 and I-kappa-B-alpha in the differentiation and functionality of T cells during an acute viral infection. These findings suggest that the modulation of FoxO1 and I-kappa-B-alpha is a promising strategy to enhance T cell responses to vaccinations or acute viral infections.