T Cell Activation: A Cholesterol Based Model

Cholesterol prevents an immune response, even when no antigen is present, University Freiburg biologists have shown.

Giving it a critical role in the activation of a T cell, cholesterol binds and stabilizes inactive receptors. T cells are able to switch their conformation from an inactive to an active state spontaneously without any antigens present, Prof. Dr. Wolfgang Schamel and Dr. Susana Minguet, immunologists from the University of Freiburg, and their team of researchers, have now shown.

Researchers previously believed that an antigen like a pathogen must bind to a T cell receptor in order to activate it, thereby triggering an immune response.

“We demonstrated that it’s not the binding to an antigen that causes the switch in the conformation; it happens spontaneously,” said Schamel.

T Cell Receptor States

The T cell receptor, which is located in the outer membrane, recognizes antigens, in other words, foreign substances, and binds them. Such a receptor can have two different structures: the resting T cell receptor in an inactive state, and the so-called primed receptor, which is in an active conformation.

In the active state, the T cell receptor sets in motion signalling pathways in the T cell that trigger an immune response – the T cell attacks the intruder. Schamel and Minguet discovered that a T cell receptor switches between these two states, even in the absence of an antigen.

When an antigen enters an organism, it can only be bound by a primed T cell receptor, that is by a receptor in the active conformation, and not by a resting receptor. When this happens, the number of active receptors increases, and the T cell is activated.

Cholesterol Synthesis

A primed receptor is sufficient to activate a T cell; no binding to an antigen is necessary. This means that, although no antigen is present, an immune response can be erroneously triggered, if there are too many primed receptors.

A certain mechanism prevents this: cholesterol, an abundant lipid in the membrane, only binds to receptors in the inactive state and thus stabilizes them. This reduces the number of T cell receptors that spontaneously can switch to the active state, and the T cell is not activated.

Only when an antigen binds to a primed T cell receptor will further receptors switch from an inactive to active state and the T cell is activated.

Because only cholesterol can bind to an inactive T cell receptor, this is a specific interaction.

“We are among the first researchers to be able to demonstrate a functional effect of an interaction of a lipid with a transmembrane protein,” said Schamel, adding: “This interaction regulates the conformation and hence the activity of the receptor.”

The cell synthesizes the necessary cholesterol itself, meaning ingesting more or less cholesterol through food does not influence the amount of this lipid in the cell membrane.

Mahima Swamy, et al.
A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation
Immunity; DOI: http://dx.doi.org/10.1016/j.immuni.2016.04.011

Image: Susana Minguet/BIOSS