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



Researchers gain insight into role of TFR, TFH cells

It has been four years since researchers discovered T follicular regulatory (TFR) cells, which work in tandem with T follicular helper (TFH) cells. The Wednesday morning ACR session T Follicular Cells and Their Mediators will cover some of the implications of this new discovery for treatment of autoimmune diseases.

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Arlene H. Sharpe, MD, PhD

Scientists are now beginning to understand it’s the ratio of TFH to TFR cells — and not absolute numbers — that determines antibody production, said co-presenter Arlene H. Sharpe, MD, PhD, George Fabyan Professor of Comparative Pathology, Microbiology and Immunobiology at Harvard Medical School.
Understanding this ratio, Dr. Sharpe said, holds promise for using it as a diagnostic or prognostic marker in patients.

The ratio can serve as a target to monitor in instances where physicians want to stimulate antibody production, such as with vaccines, or where they want to reduce antibody responses that can cause tissue damage in conditions such as rheumatoid arthritis or lupus. Dr. Sharpe said it’s unclear if TFR cells function to directly regulate B cells along with TFH cells.

“So I think it is early days, but the hope is that, as we learn more, we can translate that into new kinds of therapies,” she said.

Some of the work in Dr. Sharpe’s lab has focused on the types of molecules that control the generation and function of TFR cells, and the lab has studied several inhibitory receptors, including PD-1 and CTLA-4.

The lab has learned that TFR cells inhibit plasma cell formation, and some of its current work revolves around TFR’s implications for vaccines and for older patients, since it is known that older people don’t have as potent antibody responses as younger people.

The discovery of TFR “is causing everyone to rethink how antibody responses are regulated,” she said. “But because it’s a new cell type, one needs to really start from the ground up by asking questions about how these cells exert their inhibitory effects. And so, that is part of what we have done.”

TFR cells also hold the potential for better treatment of allergies and of chronic graft-versus-host disease in transplant patients, Dr. Sharpe said.

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Joseph Craft, MD

Based on the existence of other regulatory cells, the discovery of TFRs should not have come as a complete surprise, said co-presenter Joseph Craft, MD, Paul B. Beeson Professor of Medicine, Chief of the Section of Rheumatology, and Professor of Immunobiology at the Yale University School of Medicine.

The importance of TFH cells should not be underestimated, Dr. Craft said. Without TFH cells, people would not get lupus, ANCA-associated vasculitis, and, arguably, rheumatoid arthritis. They would also have no protections against infections, he said, since they govern our responses to vaccines.

“They activate B cells, and without them, B cells don’t properly mature to form memory and long-lived antibody secreting plasma cells, which are critical for protection against pathogens and vaccine responses,” Dr. Craft said.

New knowledge about TFH cells, he said, includes details about their development from naïve T cells and the signals that lead to such development, and that those signals include cell intrinsic signals. Those signals, including those that are cell intrinsic and those from the environment, are translated into a genetic and a metabolic program that leads to their ability to migrate to where the B cells are and to promote the function of the latter.

Dr. Craft said that investigators are also learning about how TFH cells function within the B cell follicle to form germinal centers through contact-dependent interactions and soluble interactions, leading to development of memory B cells and plasma cells in physiological and pathological circumstances, such as for vaccine responsiveness and autoimmunity, respectively.

This knowledge, he said, has implications for vaccines for treatment of lupus and other rheumatic diseases.

The session will also include Chen Dong, PhD, of Tsinghua University, who will discuss the transcriptional profile of TFH cells.