New Immune Cell Shows Therapeutic Promise

HMS researchers have identified a previously unknown cell type that is essential for preventing autoimmune diseases like type 1 diabetes and could improve cancer therapy.

The novel cell type is a subset of a group of immune suppressor cells called CD8 regulatory T cells (Tregs) and is crucial for keeping the immune system in check. The immune system requires built-in restraints to prevent it from overreacting to infection or mistakenly attacking the body’s own cells. A breakdown in the body’s capacity to tolerate its own cells may result in a variety of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE). The new population of CD8 Tregs interacts with follicular T helper cells, which support antibody-producing B cells. The result is that these CD8 Tregs dampen overzealous antibody responses. As such, the novel CD8 Tregs play a key role in immune system balance and might be harnessed to rebalance the system in cases of disruption due to disease.

“CD8 Tregs were the first suppressor subset of immune cells found, about 30 years ago,” said Hye-Jung Kim, a postdoctoral fellow at Dana-Farber Cancer Institute and first author of the study, published Sept. 16 in Nature. Yet they have not been thoroughly studied. Researchers exploring immune suppressors have focused primarily on a different group of regulatory cells, CD4 Tregs, that sport a readily identifiable protein marker on their surface, called CD25. These CD4 Tregs act to restrain excessive inflammation. The CD8 Tregs, however, control autoantibodies—antibodies targeted against the body’s own tissues. Senior author Harvey Cantor, the Baruj Benacerraf Professor of Pathology at HMS and DFCI, and colleagues had previously observed that CD8 T cells were capable of suppressing T cell support of B cells. Only now, however, has anyone defined the particular group of CD8 Tregs genetically programmed to inhibit autoantibodies.

The standard role of CD8 T cells, often called killer T cells, is to recognize microbial particles, known as antigens, displayed on the surface of infected cells and to destroy the cells. The newly discovered CD8 Tregs have a different task. They recognize a protein called Qa-1, which sits on the surface of follicular T helper cells and presents antigens that arise from excessive activation of these cells.

The researchers homed in on Qa-1 and the novel CD8 Tregs by developing a mouse model with a single amino acid mutation “knocked in” to its genome. This inserted mutation, the team discovered, alters the structure of Qa-1 enough to disrupt its ability to display antigens to the CD8 Tregs. Consequently, in these knock-in mice, the “CD8 T cells cannot see their target cells,” said Kim. So the CD8 Tregs cannot interact with the follicular T helper cells to stifle autoantibody production.

Evidence for this breakdown came when the researchers caused the mice to develop a T cell–mediated autoimmune disease that mimics multiple sclerosis, called experimental autoimmune encephalomyelitis (EAE). The animals “developed a really high level of EAE, meaning that some regulatory mechanism was not working,” Kim said. CD4 T cells were already known to be the major player in EAE, and the authors discovered that only one CD4 T cell subset, follicular T helper cells, routinely expresses high levels of Qa-1. These are the only cells “waving a flag to attract the CD8 cells,” Kim said.

Since the mice harbor a faulty suppression pathway for follicular T helper cells, they exhibit significantly increased B cell activation and differentiation (see figure). “We thought, wow! This was the first indication that our knock-in mice had a phenotype,” said Kim.

Kim and colleagues went on to demonstrate that these mice developed severe autoimmunity, like that seen in SLE, when infected with a virus. “It’s amazing—just one amino acid change made this whole difference,” Kim said.

The researchers envision two ways to harness the newly discovered CD8 Tregs for clinical use.

“In autoimmunity, we want to suppress the immune response—that’s why it is important to enhance the function or number of suppressor cells,” Kim explained.

According to Cantor, suppressor cells are especially sensitive to interleukin 15 (IL-15), a protein signal required for expansion and, perhaps, suppressive activity of the CD8 Tregs. “We do have preliminary data in an arthritis model which suggests that injection of IL-15 inhibits the development of the disease,” he said.

Alternatively, “in tumor immunity, suppressors are bad guys: they inhibit antitumor responses. That’s why we want to remove their activity in cancer patients,” said Kim. One possibility is using Qa-1 antibodies to specifically remove CD8 Treg–mediated suppression, which would “immediately enhance the antitumor antibody response in cancer patients,” said Kim, who has tested this theory in a mouse tumor model.

“At the end of the day, it may turn out that there is a division of labor between the two major types of regulatory cells [CD8 and CD4] that might be useful in terms of designing clinical protocols,” said Cantor, who is a member of the Harvard Committee on Immunology (see Harvard Immunology). Intensive research continues to further define these CD8 Tregs. “It’s still early days, but so far the impact of these cells on their major target, follicular T helper cells, has been fairly impressive.”

For more information, students may contact Harvey Cantor at Harvey_Cantor@dfci.harvard.edu.

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: The National Institutes of Health, the Lupus Research Institute, the Schecter Research Foundation, NRSA Fellowships and a Belgian American Educational Foundation Fellowship; the authors are solely responsible for the content of this work.

Disclaimer: The researchers are unable to provide treatment recommendations for individual cases.