Michael Scaglione

“The MLX family of metabolic transcription factors in immune cell activation”

Michael Scaglione, Will Bailis

Immune cells have recently gained attention for their incredible dynamism in cellular metabolism. Upon activation, these cells radically rewire their metabolic networks to divert biochemical molecules needed for proliferation, differentiation, and cytokine secretion. Immune cells, especially tissue-resident cells, must also constantly sense and respond to changes in their metabolic environment that often accompany infection or changes in homeostasis. However, work is only starting to reveal the mechanisms by which immune cells translate information about their metabolic environment into their lineage- and tissue-specific functional programs.

My current work focuses on the integration of nutrient sensing by the MLX family of transcription factors into programs of immune cell activation and function. MLX family members directly sense glycolytic intermediates and divert these products into anabolic processes including de novo lipogenesis and nucleotide biosynthesis. These processes are highly leveraged by proliferative immune cells such as lymphocytes. Thus, I hypothesize that MLX supports lymphocyte activation by coordinating the engagement of anabolic metabolic networks necessary for proliferation. Preliminary data I have collected suggests that MLX activity may be required for the proliferation and function of CD4+ T cells.

Immune cells often function in unique tissue niches that vary widely in their metabolic content. Additionally, altered diet or metabolic disease can disrupt global organismal metabolism, shifting the immunologic response to infection or altered homeostasis. Recent work suggests that MLX activity is dynamically modulated by a cell’s internal metabolic state and external environment. I hypothesize that the MLX family is a key sensor of the metabolic microenvironment in immune cells, integrating information about sugar, lipid, and ketone body availability into changes in functional programming. I aim to test the role of MLX family members in linking changes in metabolic state to alterations in immune cell function using in vitro culture systems as well as in vivo dietary interventions.