Study Finds New Role for TOX Protein in Immunity

Corey R. Seehus

In a newly published study, Cedars-Sinai scientists shed light on how the body constructs its disease-fighting immune system. Their data showed for the first time that a protein known as TOX is critical to the process by which the bone marrow generates precursors for certain types of immune cells. The study was based on genetically modified mouse models, one of which was created at Cedars-Sinai.

The first author of the study, who was instrumental in developing this line of investigation, was Corey R. Seehus, a graduate student in the laboratory of the principal investigator, Jonathan Kaye, PhD. Kaye is director of the Research Division of Immunology and professor and vice chair of Biomedical Sciences. His lab previously has performed a series of pioneering studies on TOX (thymocyte selection-associated HMG-box protein) and its role in immunity.

Crystal structure of the TOX DNA-binding domain, in collaboration with Ramachandran Murali, PhD.

The new study, published online April 27 by the journal Nature Immunology, focused on innate lymphoid cells, or ILCs — building blocks of the innate immune system. This system marshals the body's first response to infectious agents that we encounter during our lives.

The diversity of ILCs has only been appreciated over the last five years. But already there is data on the key role of these cells in protective immune responses, including epithelial cell repair following influenza infection. The data also indicates a role for ILCs in a number of conditions, including asthma, allergies, pulmonary and liver fibrosis, metabolic diseases, inflammatory bowel disease and cancer.

"The identification and characterization of ILCs has led to considerable advances in understanding of the cellular mechanisms that underlie immunological responses during homeostasis and disease," the researchers wrote. And yet, they explained, "how progenitor cells in the bone marrow give rise to multiple ILC lineages is not well understood." Their study sought to bridge that knowledge gap.

Jonathan Kaye, PhD

The researchers found that TOX, a protein that regulates gene expression, was required for development of a bone marrow progenitor cell that gives rise to all ILC subtypes. In collaboration with the Cedars-Sinai Genomics Core, they were able to perform whole transcriptome sequencing on the very few ILC progenitor cells that are found in an animal. This sequencing allowed them to pinpoint the exact molecular defects that existed in bone marrow cells that lacked TOX.

The study led to novel insights into how multipotent progenitor cells are driven to become certain immune cells. In continuing work, the Kaye lab plans to elucidate the molecular mechanisms involved, Kaye said.

Several Cedars-Sinai staff members, in addition to Seehus and Kaye, collaborated on the study. They included:

  • Parinaz Aliahmad, PhD, project scientist
  • Brian de la Torre, research associate
  • Iliyan Iliev, PhD, research scientist and postdoctoral fellow
  • Lindsay Spurka, research associate
  • Vincent A. Funari, director of the Cedars-Sinai Genomics Core