Solution to Immune Mystery Could Lead to Better Therapies

LA JOLLA, CA—November 13, 2013—A team led by scientists at The Scripps Research Institute (TSRI) has solved a long-standing conundrum about the immune system and in so doing may have found a new way to boost or reduce immunity therapeutically.

The discovery concerns an unusual protein, Themis, that has been known to play a key role in the normal development of T cells, one of the most powerful elements of the immune system. Exactly how Themis controls T cell development hasn’t been clear. But now in a report in the journal Nature, the TSRI scientists have described how the protein subtly but crucially ensures the maturation of T cells that are fit for active duty in the body.

“We’ve finally cracked the mystery of how Themis works, and we suspect that this finding will turn out to have relevance for human diseases,” said immunologist Nicholas R. J. Gascoigne, who led the work at TSRI.

Unraveling the Selection Process

Themis functions during a critical phase of T cell development within the thymus, a small, two-lobed gland in the chest behind the sternum. Immature T cells originate in the bone marrow and then migrate to the thymus, where they undergo a selection process that determines whether they will be allowed to mature and circulate in the blood. In this selection process, the young T cells (thymocytes) are presented with a variety of protein fragments from the body’s own cells. The thymocytes that react too strongly to these “self antigens,” and thus could trigger autoimmune disease if allowed to mature, are made to self-destruct. The rest are prompted to mature and to graduate to the circulatory system, where they guard the body against infections and cancers.

The details of this selection process have long been murky to immunologists, but in 2009 Gascoigne’s TSRI laboratory and several others reported the discovery of a major clue: a protein, dubbed Themis (“thymocyte-expressed molecule involved in selection”), whose absence seriously disrupts the thymocyte selection process in mice. In Themis-less mice, relatively few T cells graduate from the thymus, leaving the animals with a major immune deficiency. The researchers observed that Themis’s gene is expressed almost exclusively in thymocytes—another strong hint that Themis evolved to guide T cell development. Themis also turned out to be present in virtually all vertebrate animals, underscoring its likely importance for survival.

Yet Themis otherwise would not yield up its secrets. It bore little resemblance to any known protein family. “Because it was so unusual, we didn’t have a good handle on how to study it,” said Gascoigne. His and other laboratories were unable to determine conclusively how the protein regulates thymocyte selection. In lab dish experiments they simulated the presentation of self antigens to normal thymocytes and Themis-less thymocytes, but saw little difference in the thymocytes’ reactions.

A Different Approach to the Problem

In their new paper, Gascoigne and his colleagues have described how they finally were able to determine Themis’s elusive function.

The key was to model thymocytes’ interactions with self antigens more realistically. Previous experiments had stimulated thymocytes in a traditional but relatively artificial way, using antibodies that bind with high affinity to the cells’ main, antigen-grabbing receptor, known as the T cell receptor. “Immature T cells usually receive more mild stimulations in the thymus of a live animal,” said Guo Fu, a staff scientist in in TSRI’s Department of Immunology and Microbial Science who was lead author of the new study, and also of the 2009 study.

Fu, Gascoigne and their colleagues thus decided to try lesser stimulation strengths, using other molecules that bind to the T cell receptor with a range of affinities. “The new approach involved a tremendous amount of work, because we had to do the experiments using nine or ten different receptor-binding molecules, rather than just one,” Fu said. “But it paid off.”

The experiments showed that Themis plays a role in thymocytes not during strong affinity interactions but during weak and intermediate-affinity interactions—the kind that would be expected when “good” thymocytes, suited for battling foreign antigens, encounter self antigens instead. In such interactions, the team determined, Themis activates an enzyme called SHP1, which in turn suppresses the internal signal induced by T cell receptor stimulation.

Themis therefore turns moderate or weak stimulation into the specific signals that allow the thymocyte to survive and become a mature T cell. Without this signal-damping effect, even the thymocytes that are not potentially autoimmune, and that would have become the “repertoire” of T cells available to recognize foreign antigens, would be stimulated so strongly in the thymus that they self-destruct most of the time.

Opening Doors

The discovery helps scientists understand better how T cells develop, and of course points to the possibility of better therapeutic methods for controlling immunity. Studies already have linked variants in the Themis gene—which possibly increase its production excessively—to two autoimmune conditions: multiple sclerosis and the inflammatory gut ailment known as celiac disease.

Targeting Themis during thymocyte development might be risky, but the protein, and SHP1, are also expressed in small amounts in mature, circulating T cells. That hints that Themis may play a role in regulating the activity of these cells, too. “If it does, we could have a very useful way to change the strength of the immune response to a specific target, for example a tumor,” said Gascoigne.

Fu notes too that immune-modulating drugs in current use tend to have relatively broad and dramatic effects on the immunological processes they target. “In principle, targeting a more subtly acting ‘tuner’ such as Themis could allow us to dial immunity up or down more precisely, with fewer side effects,” he said.

Other contributors to the study, “Themis sets the signal threshold for positive and negative selection in T cell development” (doi: 10.1038/nature12718), were Javier Casas, Stephanie Rigaud, Vasily Rybakin, Joanna Brzostek, John A.H. Hoerter and Karsten Sauer of TSRI; Oreste Acuto and Wolfgang Paster at the University of Oxford; and Hilde Cheroutre and Florence Lambolez of the La Jolla Institute for Allergy and Immunology. Gascoigne is currently adjunct professor at TSRI and head of the Department of Microbiology at National University of Singapore’s Yong Loo Lin School of Medicine.

The study received support from the National Institutes for Health (AI073870, DK094173, GM065230, DP1OD006433, GM100785 and AI070845), the Wellcome Trust (GR076558MA) and the National University of Singapore.

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