Researchers led by Hannah Meyer, PhD, Cold Spring Harbor Laboratory Fellow, published a paper “Transcriptomic diversity in human medullary thymic epithelial cells” in Nature Communications that describes how the human thymus generates a list of  healthy proteins that T cells should not attack. Her team identified, for the first time, the RNA molecules used to generate this list that protects healthy tissue from T cells.

Their discovery may help identify key differences between effective and flawed immune systems and lead to improved autoimmune disorder treatments.

“The induction of central T cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs). This promiscuous gene expression (pGE) drives mTEC transcriptomic diversity, with non-canonical transcript initiation, alternative splicing, and expression of endogenous retroelements (EREs) representing important but incompletely understood contributors,” write the investigators.

“Here we map the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5’ cap and RNA sequencing. Both mTEC populations show high splicing entropy, potentially driven by the expression of peripheral splicing factors. During mTEC maturation, rates of global transcript mis-initiation increase and EREs enriched in long terminal repeat retrotransposons are up-regulated, the latter often found in proximity to differentially expressed genes.

“As a resource, we provide an interactive public interface for exploring mTEC transcriptomic diversity. Our findings therefore help construct a map of transcriptomic diversity in the healthy human thymus and may ultimately facilitate the identification of those epitopes which contribute to autoimmunity and immune recognition of tumor antigens.”

No other organ in the body makes every possible protein

To attack the right targets, T cells need a thorough education about the proteins they might encounter in the human body. The human body can produce around 20,000 different types of proteins. Before T cells leave the thymus to fight infections, they must be trained to recognize all of these friendly proteins. This means the thymus has to make all 20,000 proteins. No other organ in the human body makes every possible protein. They only make the proteins needed for their specific organ function.

“Usually, it is very strictly regulated which proteins are made in which cells and tissues. Thymus cells make all of them to ensure the immune system functions properly,” Meyer says.

She focuses on the thymus for its role in not just preventing autoimmune diseases but for also fighting infections and cancer. Meyer hopes these diseases can be better understood and treated by further exploring the proteins made in the thymus. Meyer’s new list is available to other researchers in an interactive online database.

To learn more about Hannah Meyer and the work she’s doing to understand the immune system, please see “How does anyone stay healthy in a world full of germs?