Latest Discovery in Metabolic Pathways of T-Cells Opens New Door to Immunology Research

Researchers from the University of Michigan Rogel Cancer Center successfully developed an in vitro culturing system that feeds T cells differently from conventional cultures. 

With findings published in the journal Science Immunology, the team modified a standardized culture medium and found that T cells cultured under their experimental conditions resembled their in vivo counterparts in terms of metabolic behavior. This new approach enables observation in the lab of how different modes of metabolism regulate T-cell persistence in living organisms.

Related article: Overcoming Immune Evasion in CAR-T Therapies with Groundbreaking New Discoveries 

Metabolic Pathways Hold the Key to T-Cell Functions

The research team, led by Prof. Costas A. Lyssiotis, Maisel Research Professor of Oncology at the Rogel Cancer Center, focused on a specific type of CD4+ T cell called T_H17, T helper cells that produce interleukin 17 family cytokines (IL-17) in their investigation. T_H17s are involved in adaptive immunity that protects against infections and cancers. On one hand, T_H17s are important players in mucosal immune responses against infectious pathogens, the immune system will be weakened if their persistence is too low. On the other hand, if T_H17s become overactive, autoimmunity may develop, leading to possibly devastating autoimmune diseases.

According to Hanna S. Hong, a graduate student in immunology at the University of Michigan and the first author of this study, the metabolic pathways of T cells determine their specific identities and functions. The inner workings of each type of T cell are therefore distinct from each other. For living cells including T cells, glycolysis and oxidative phosphorylation (OXPHOS) are two major metabolic pathways through which they harness energy from food molecules, while OXPHOS is more efficient than glycolysis in terms of energy production (in the form of ATP). 

Prior research has indicated that the mechanism by which cells convert nutrients into energy in living organisms is very different from how metabolism is modeled in the laboratory, a disparity that has hindered the translation of existing research into the real world. Unlike standardized culture conditions that predominately make T_H17s use the glycolytic pathway, Hong developed a type of “cell food” to grow T_H17s in a culture that induces their OXPHOS dependence. The team discovered that T_H17s cultured under OXPHOS conditions metabolically resembled T cells in an organism, whereas glycolytic cultures were dissimilar.

Oxidative Phosphorylation Enhances T-Cells’ Persistence and Apototic Resistance

One of the most significant findings from the team was that T_H17s grown under OXPHOS conditions had an increased persistence. OXPHOS made T_H17s exhibit limited mitophagy and increased mitochondrial fitness. Also, they showed a phenotype that is more resistant to apoptosis, marked by a higher level of BCL-XL (an anti-apoptotic protein) and a lower level of BIM (a proapoptotic protein). By contrast, glycolytic T_H17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. 

In addition, researchers found that OXPHOS protects T_H17s from apoptosis in a murine melanoma model. Overall, this study demonstrated that metabolism can control the fate of T_H17s and highlighted the possibility of treating diseases that are driven by T_H17s by targeting OXPHOS. 

Opening New Doors to Immunology Research

As Hong noted, T_H17 cells can take on properties associated with autoimmunity and immune suppression because different metabolic pathways are available to them. “We’re dedicating more effort to understanding the underlying mechanisms that cause T_H17 cells to transition from those that protect against infections to those that promote autoimmunity. Ultimately, the hope is that targeting these pathways can reverse disease,” said Hong.

Author

Richard Chau