mTORC1, the ‘Sorting Hat’ of the thymic school

The development of specialized cells of the immune system is shaped by a series of well-characterized events and cell-to-cell interactions. Like the Sorting Hat that sorts new students at Harry Potter’s alma mater, Hogwarts, we have discovered that the molecular complex mTORC1 sits at the interface of lymphocyte fate choices. mTORC1 integrates intrathymic environmental signals and metabolic programs to drive thymocyte development.

The “T” defense

The immune system is in charge of defending the body against infection and other diseases. Like any defense system, it acts as a network of multiple players with various roles. These cellular players interact with each other to mount immune responses.

One important player in the immune system is the T cell. T cells are specialized white blood cells that recognize and attack cells that have been infected with viruses or other intracellular pathogens, or that have become cancerous.

In the St. Jude Children’s Research Hospital lab of Hongbo Chi, PhD, we are particularly interested in understanding the signaling mechanisms and metabolic pathways that control the differentiation and function of T cells. Simply put, we aim to identify the molecular signals that trigger these commando-like cells.

Supporting the cause

The work of our team and of others around the world have highlighted the central role that metabolic reprogramming plays in T cell-mediated immune responses. We now know that the metabolic processes T cells engage, once T cells receive the call-to-action signals, are linked to the type of response or behavior they display.

These observations have opened a window of therapeutic opportunities to boost immune responses against cancer and infectious diseases and to control autoimmunity.

What’s your lineage decision?

Immunometabolism is the study of the interactions between the immune system and metabolic processes at the cellular level. An unanswered question in this field is whether specific metabolic signals drive lineage decisions during T cell development. You can think of a lineage decision as T cells picking a college major, with the thymus serving as the college for T cells. In the thymus, developing T cells undergo a series of developmental processes that result in the differentiation of two distinct T cell lineages: alpha-beta (αβ) and gamma-delta (γδ) T cells.

This nomenclature, or given title, is based on the structure of the T cell receptor these cells express on their surface when they complete development. Similar to the contrasting views about life and careers that art and business majors have during their senior year of college, αβ and γδ T cells are fundamentally distinct and have discrete roles in the immune system.

It is known that the interaction of various extrinsic and intrinsic factors governs T cell lineage commitment. However, the mechanism linking such signals to lineage commitment, or the Sorting Hat, had remained elusive.

mTORC1 and T cell development

Our curiosity about the role of metabolic signals in T cell development led us to the discovery of the T cell’s Sorting Hat: mTORC1.

The mechanistic target of rapamycin, mTOR, is a molecule that acts as a central sensor that integrates immune signals and metabolic cues in orchestrating T cell function and fate. mTOR exists in two multiprotein complexes: mTOR complex 1 (mTORC1), which contains the scaffolding protein RAPTOR, and mTORC2, which has a different scaffolding protein, RICTOR.

We found that developing thymocytes engage in dynamic regulation of metabolic and mTORC1 activity. When we disabled mTORC1 activity in developing T cells by genetically deleting RAPTOR, we observed a dramatic shift in T cell lineage commitment: αβ T cell development was impaired whereas γδ T cell development was promoted.

Conventional or unconventional?

This shift in T cell lineage commitment, from αβ to γδ, was intriguing to us because the vast majority of T cells in the body are αβ T cells. In fact, αβ T cells are considered "conventional T cells," as they largely outnumber γδ T cells; αβ T cells reside in lymphoid organs and are constantly recirculating the body through the blood. On the other hand, γδ T cells are scarce. Typically found only in the gut mucosa, skin and other barrier tissues, γδ T cells are referred to as "unconventional T cells."

In an effort to identify the mechanism behind our observation, our studies revealed that RAPTOR deletion led to the disruption of metabolic remodeling of oxidative and glycolytic metabolism. Such disruption was followed by the excessive production of reactive oxygen species (ROS)—highly reactive byproducts of oxidative phosphorylation—that impinged upon T cell fate decisions.

The mTORC1 checkpoint

The collaborative nature of the research at St. Jude allowed us to perform both single-cell RNA sequencing and transcriptomic analyses of RAPTOR-deficient thymocytes. These cutting-edge analyses revealed the key roles of mTORC1 in coordinating anabolic metabolism and signal strength, which ultimately control T cell lineage choices.

Altogether, our work is the first to establish mTORC1 signaling as a developmental checkpoint that links intrathymic environmental signals and metabolic programs to drive thymocyte development. This is a significant step in understanding how the cells that help us battle cancer and infectious diseases get made in the first place.

Our lab is committed to understanding the fundamental signaling mechanisms and metabolic pathways that underlay T cell function and regulation. By expanding our current knowledge of T cell biology, we hope to explore innovative therapeutic opportunities that will advance and improve treatments of cancer and other diseases.