Lineage-specifying transcription factors coordinate a diverse array of cellular processes for the appropriate differentiation of the cell. In CD4+ T cell, the T-box transcription factor T-bet is required for the development of T helper type 1 (Th1) cells, whereas the BTB-zinc finger (ZF) factor Bcl-6 is required for T follicular helper (Tfh) cell development. Importantly, the balance between these two lineage-specifying factors also influences the effector versus memory cell transition in CD4+ and CD8+ T cells. To date, our understanding of the gene expression programs that the balance between T-bet and Bcl-6 regulate to control the effector versus memory transition have been incomplete. Recent research in the field has highlighted the importance of metabolic states in the differentiation and functional potential of immune cells. In T cells, a high rate of glycolysis is needed for effector ell differentiation whereas the glycolysis pathway is dampened in favor of the fatty acid oxidation (FAO) pathway in memory cells. Notably, artificially inhibiting the glycolytic pathway in CD8+ T cells can effectively promote memory cell differentiation. Thus, the regulation of cellular metabolism is important for the effector versus memory cell transition and targeting the metabolic state of T cells represents a novel way to control this decision in autoimmune states and vaccine strategies. In new research from my laboratory, we have shown for that the balance between T-bet and Bcl-6 is important for the IL-2-sensitive regulation of the glycolysis gene expression program. Our new data suggest that at least in part, the close connection between cellular metabolism and differentiation states is because these processes are mechanistically regulated by a similar complement of lineage-specifying transcription factors. In this proposal we will define how different environmental conditions in vitro and microenvironments in vivo influence the expression of the metabolic gene program and metabolite accumulation in effector versus memory T cells, and determine the role for the balance between T-bet and Bcl-6 in these processes. We will also define the role for metabolites in regulating specialization programs in T cells and whether T-bet and Bcl-6 contribute to targeting their activities. This is a critical new direction of research to pursue because it has the potential to provide new therapeutic opportunities to redirect immune cell differentiation using clinically approved metabolic inhibitors. In the case of memory cell development, this will aid in vaccination strategies for viruses such as HIV and HCV where robust long-term memory responses have not yet been achieved. For autoimmune conditions, this has the potential to dampen the aberrant activities that cause tissue specific pathologies. Therefore, the basic knowledge gained in these studies will increase our future potential to logically target metabolic pathways to enhance immunity and treat conditions caused by pathogenic immune responses.

Public Health Relevance

Lineage-specifying transcription factors play a critical role in controlling immune cell development. Aberrant expression of these factors result in pathogenic states such as immune disorders, failure to control infections, ineffective vaccines and blood cancers. Our studies will define the role for lineage-specifying transcription factors in translatig environmental signals into distinct cellular metabolism and specialization states.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Mallia, Conrad M
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University of Alabama Birmingham
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Chisolm, Danielle A; Weinmann, Amy S (2018) Metabolites, genome organization, and cellular differentiation gene programs. Curr Opin Immunol 51:62-67
Chisolm, Danielle A; Savic, Daniel; Moore, Amanda J et al. (2017) CCCTC-Binding Factor Translates Interleukin 2- and ?-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs. Immunity 47:251-267.e7
Gibson, Sara A; Yang, Wei; Yan, Zhaoqi et al. (2017) Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation. J Immunol 198:4244-4254
Botta, Davide; Fuller, Michael J; Marquez-Lago, Tatiana T et al. (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18:1249-1260
Hough, Kenneth P; Chisolm, Danielle A; Weinmann, Amy S (2015) Transcriptional regulation of T cell metabolism. Mol Immunol 68:520-6
Weinmann, Amy S (2014) Regulatory mechanisms that control T-follicular helper and T-helper 1 cell flexibility. Immunol Cell Biol 92:34-9
Oestreich, Kenneth J; Read, Kaitlin A; Gilbertson, Sarah E et al. (2014) Bcl-6 directly represses the gene program of the glycolysis pathway. Nat Immunol 15:957-64
Weinmann, Amy S (2014) Roles for helper T cell lineage-specifying transcription factors in cellular specialization. Adv Immunol 124:171-206
Buckingham, Kati J; McMillin, Margaret J; Brassil, Margaret M et al. (2013) Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats. Mamm Genome 24:400-8
Oestreich, Kenneth J; Weinmann, Amy S (2012) T-bet employs diverse regulatory mechanisms to repress transcription. Trends Immunol 33:78-83

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