T lymphocytes, or T cells, are a type of white blood cell essential to the immune system. These cells are part of the adaptive immune response and serve as trained guards for the body, finding and eliminating threats such as viruses and harmful bacteria.
T cells develop from precursor cells that travel from the bone marrow to the thymus where they mature and specialize. The cells undergo a series of differentiations and eventually split in to two distinct lineages, alpha beta and gamma delta, based on the protein chains on the cell. Alpha beta cells are considered conventional T cells, they circulate throughout the body and reside in the spleen and lymph nodes. Gamma delta cells are considered unconventional, found in smaller numbers, and reside in the gut, skin and other barrier tissues. Dr. Hongbo Chi of St. Jude’s Immunology Department said “We know that conventional and unconventional T cells are fundamentally different, they express different cell surface receptors. The cells have different functions. But until now the mechanism that helps decide their fates has remained largely unknown.”
While previous studies have focused on the effects of certain proteins like NOTCH and interleukin-7 on cell survival and growth, no studies have found a specific link between metabolic signals and lineage decisions or the interplay of metabolism with immune signals. Emerging studies have shown the involvement of rapamycin (mTOR) in integrating metabolic cues and immune signals to orchestrate T cell function and fate. But the role of mTOR signaling in T cell lineage fate between alpha beta and gamma delta has yet to be elucidated, until recently.
A study from St. Jude’s Department of Immunology has shed some light on the mechanism behind T cell differentiation to alpha beta or gamma delta. Dr. Chi and his colleagues utilized genetically engineered mouse models to further elucidate the role of a protein complex, mTORC1, and its role in the fate of T cells.
Activation of this protein complex increased energy production via anabolic metabolism leading to increased development of alpha beta T cells. On the flip side, the mTORC1 complex was disabled by genetic deletion of the protein RAPTOR that is involved in the complex. This resulted in metabolism disruption, which resulted in an increase in gamma delta cells and a decrease in alpha beta cells. This deletion not only resulted in reduced anabolic metabolism but increased the level of reactive oxygen species (ROS), which is toxic to cells, and promoted cell growth by upregulating certain molecular pathways. This study showed that mTORC1 integrates both metabolic and signaling activity to dictate the fate of T-cell lineage and control ROS production as a key signal in this process.
"This research establishes mTORC1-driven metabolic signaling as a decisive factor in determining the fate of developing T cells and suggests metabolic processes are a fundamental mechanism that connects external signals with internal processes to guide the fate of immune cells," Chi said.
To read this study click here. To learn more about T cells and their role in the adaptive immune response watch the video below.