THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Engleman lecture to tell history of T cell signaling

This year’s Rheumatology Research Foundation Memorial Lecture Honoring Dr. Ephraim Engleman will trace the story of T cell signaling.

T cells are both heroes and villains. In most individuals, T cell response is a key step in the immune response that protects the body from pathogens or cancer. Normal signaling pathways produce a normal immune response; abnormal pathways may produce a pathogenic response. The ways in which T cells respond to antigens is controlled largely by T cell signaling pathways.

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Arthur Weiss, MD, PhD

“In order to have a balanced immune system, you have to have strong enough T cell signaling to effect regulatory mechanisms,” said Arthur Weiss, MD, PhD, Ephraim P. Engleman Distinguished Professor at the University of California, San Francisco, and Howard Hughes Medical Institute Investigator. “Perturbations in the signaling mechanism can result in immunodeficiency and autoimmunity and the associated diseases. We are beginning to understand how the complexities of T cell signaling are regulated and what the key nodes of regulation are. As we are beginning to see in cancer therapy, those key nodes would be great therapeutic targets.”

Dr. Weiss will present T Cell Receptor Signaling from 7:30 – 8:30 am on Tuesday. When he began investigating T cells in the 1980s, the mechanisms by which they functioned and malfunctioned were little more than a black box. The only thing that was clear was that something interacted with cells to affect genes that had something to do with growth factors, cytokines, and lymphokines to produce disease.

“Very few genes had been cloned at that point, and we knew next to nothing about the processes involved,” Dr. Weiss remembered. “It seemed hopeless to try to understand how to treat autoimmunity diseases like rheumatoid arthritis and lupus if we didn’t understand the fundamental mechanisms involved in turning on or off the immune system. Quite honestly, what we knew was that we didn’t know much of anything about normal immune function and even less about abnormal immune function that could lead to disease.”

T cells have emerged as key players in a variety of rheumatologic diseases. They are activated by way of signaling mechanisms that are controlled by the T cell antigen receptor, he said. Genetic defects that affect receptor signal transduction can result in autoimmunity, immunodeficiency, and sometimes both conditions in the same individual.

One of the early keys was the discovery of selective T cell immune deficiency because of loss-of-function mutations in Zap70, a protein kinase discovered in the Weiss lab. The more recent discovery of a single family in which the children developed autoimmune skin disease, kidney disease, inflammatory bowel disease, and acquired hemophilia as a result of mutations affecting regulation of Zap70 emphasizes the critical importance of proper regulation of this kinase.

Many cytokines interact with receptors that depend on the functions of the Janus kinases, or JAK family of enzymes. JAK inhibitors such as tofacitinib disrupt inflammatory cytokine signaling pathways and are being used to treat rheumatoid arthritis. Tofacitinib targets the catalytic site of the enzyme, but there are no known similar inhibitors of Zap70. A new strategy from the Weiss lab targets allosteric sites in Zap70, interfering with its three dimensional conformation and altering its activity. A similar strategy can be used to target other kinases.

Another approach to controlling T cell function involves genetic manipulation to rewire T cells and disrupt cell signaling. This is already being used in cancer therapy.

Chimeric antigen receptors, a technology pioneered in the Weiss lab, has led to genetically modified chimeric antigen receptors that have transformed childhood B cell leukemia from a disease with a 20 percent long-term survival rate into an 80 percent survival rate. Similar efforts in T cell receptor modification will likely make inroads into autoimmune disease.

“We are going to have to understand how to dial up and dial down signaling pathways to achieve therapeutic responses,” he explained. “That will happen with being able to choose and titrate the doses of the therapeutics we use more accurately in the specific patient, as well as developing new therapeutics, and likely some genetic engineering of somatic cells to rewire their signaling circuity. There are multiple biotech and pharma companies taking up this genetic rewiring technology. We will likely see new therapeutic approaches along these lines in our lifetime.”

CLINICAL SCIENCE TRACK
T Cell Receptor Signaling
7:30 – 8:30 am Tuesday • Hall E