Supercomputer uncovers immune system's secret to self-tolerance

A discovery published in Nature Immunology has shed light on why the immune system is less aggressive toward self-antigens, offering new opportunities to enhance cancer immunotherapy.

Researchers from the La Jolla Institute for Immunology recently used the Expanse supercomputer at the San Diego Supercomputer Center (SDSC), which is a pillar of the School of Computing, Information and Data Sciences (SCIDS) at UC San Diego, to better understand how cancer tumors react when the immune system is used to combat them.

"Our study used both computational models created with Expanse and laboratory experiments to explore how immune cells called CD4⁺ T cells respond to self-antigens," explained Klaus Ley, currently co-director of the Immunology Center of Georgia and previously a professor at the La Jolla Institute for Immunology and faculty-affiliate in the Bioengineering Department at the UC San Diego Jacobs School of Engineering.

"We found that part of the weaker response is due to negative selection—a process that eliminates overly reactive T cells in the thymus—as well as a more significant factor: two proteins (PD-1 and CD73) which suppress the activity of self-specific CD4⁺ T cells."

Ley explained that the models run on Expanse via allocations on ACCESS—a program established by the U.S. National Science Foundation (NSF)—and the laboratory experiments showed that blocking PD-1 and CD73 with genetic or pharmacological methods boosted the response of self-specific CD4⁺ T cells, enabling them to behave more like foreign-specific cells.

He said that this finding highlights how PD-1 and CD73 act synergistically to dampen immune responses to self-antigens—maintaining tolerance and preventing autoimmunity.

"The collaboration brought together teams with complementary areas of expertise to achieve results that might not have otherwise been possible, hopefully one day leading to improvements in the treatments of cancers that exploit tolerance mechanisms to evade immune detection," said Bob Sinkovits, a senior computational scientist and Expanse co-principal investigator at SDSC.