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Competition for Survival Signals Maintains Immune Balance

Scarce innate lymphoid cells vie with T cells for a shared source of interleukin-7

LA JOLLA, CA – July 24, 2017 –An international team of scientists have learned that the recently discovered and relatively rare innate lymphoid cells (ILC) can exert measurable control over the survival of the mighty T cells. Led by Charles D. Surh, Director of the Academy of Immunology and Microbiology (AIM) at the Institute for Basic Science, the research drew on crucial discoveries from work started at The Scripps Research Institute (TSRI) and completed at La Jolla Institute for Allergy and Immunology and AIM.

Published this week in the journal Immunity, the new study reveals that as a minority population, the innate lymphoid cells possess a mechanism that enables them to outcompete the majority T cells for interleukin-7 (IL- 7), a shared resource needed for the survival of both. Through such a mechanism, innate lymphoid cells, which are involved in the resistance to pathogens, tissue remodeling and immune disorders, can be maintained in vivo to ensure the cellular and functional diversity of the immune system. These findings are not only of interest to the esoteric field of immune homeostasis, but also to the broad biological community because they reveal an instance of cell-to-cell communication that does not conform to the classical direct model (e.g. cell A expresses a product to influence the behavior of cell B), but rather to a more layered, indirect model (e.g. cell A influences cell B by limiting access to a product expressed by cell C).

IL-7’s Mysterious Role in Immune Cell Survival

The study of the immune system has produced many life-saving discoveries, the greatest of which is arguably the concept of immunization and immunological memory. Vaccines protect us by providing specific stimulation of populations of B and T cells that are responsive to the components in the vaccine, thereby ensuring that these select cells are ready and waiting if we encounter the pathogen for which the vaccine was designed to prepare us.

The ingredients of the vaccine are relatively short-lived, and soon the cells that were specifically activated can no longer rely on direct stimulation from the vaccine for growth and survival. However, the protective effects of the vaccine can last for many decades because of a complex system of homeostatic factors that support the survival of the vaccine-specific cells during the period between stimulations by the vaccine and pathogen. The homeostatic survival of B and T cells is not only important after vaccination, but also in old age when production of B and T cells slows and we are heavily reliant on the long-term survival of the cells we created when we were young.

The cytokine IL-7 is the immune system’s archetypal homeostatic factor. For T cells in particular, IL-7 is the primary survival signal during homeostasis. Moreover, observations from various human diseases and mouse models demonstrated that the availability of IL-7 was the key determinant of the size and naiveté of the resting T cell pool. However, in spite of scientists’ knowledge of IL-7’s crucial role in dictating T cell homeostasis, it was unclear how the body regulates the availability of IL-7 in order to ensure T cell homeostasis. The question was compounded by the difficulty of measuring IL-7 levels in vivo: traditional methods of detection were woefully inadequate to even detect (let alone quantify) IL-7 in mouse tissues.

A New Contender for IL-7 Emerges

Dr. Chris Martin, a graduate of The Kellogg School of Science and Technology and first author of the study, along with fellow researchers made their initial breakthrough discovery thanks to the Surh Lab’s success, cultivated over several decades, in characterizing the spontaneous homeostatic T cell proliferation in lymphopenic (i.e. T cell-depleted) mouse models, which occurs in response to elevated amounts of IL-7. In this new study, the researchers built upon the observation that IL-7 levels were deregulated in mice that cannot express the IL-7 2 receptor (IL-7R) because the gene has been knocked out (IL-7Rko mice).

In normal healthy mice, IL-7 is too scarce to provide the amount of stimulation that is required for T cells to undergo homeostatic proliferation. However, in the absence of IL-7R, IL-7 accumulates to supraphysiogical levels that are sufficient to drive T cell homeostatic proliferation. Using homeostatic proliferation as a method to detect excess IL-7, the group replaced various IL-7R-expressing cell types in IL-7Rko mice and monitored for a return of IL-7 homeostasis.

These experiments demonstrated that IL-7 homeostasis is maintained when IL-7R is expressed by cells of the that arise from stem cells in the bone marrow. This finding was consistent with the pre-existing idea that T cells (themselves of the bone marrow lineage) consume IL-7 and thereby decrease IL-7 availability for other T cells. However, the results clearly indicated that T cells were not the only consumers of IL-7. Martin and his colleagues probed further and identified the recently discovered and ultra-rare innate lymphoid cells as the other major IL- 7-consuming cell type.

“To be honest, I was quite surprised that ILC have such an effect in this model,” said Dr. Martin. “Relative to T cells, there are very few ILC in the tissues we study. So, when we were designing the initial experiments, we weren’t optimistic that we would find anything interesting.”

The second pivotal set of discoveries were made possible by the unique facilities of the Academy of Immunology and Microbiology in Korea. The state-of-the-art germ-free mouse facility allowed Martin’s team to eliminate the contribution of the commensal bacteria, which can induce proliferation in lymphopenic mice and confound interpretation of results.

Additionally, although ILC have recently been implicated in controlling T cell responses to commensal bacteria, the current studies showed that ILC compete for IL-7 independently of the commensal bacteria. Finally, in work led by investigator Kwang Soon Kim, the researchers demonstrated the molecular mechanism that makes ILC more effective than T cells in consuming IL-7. This is possible because the expression of IL-7R is differentially regulated in the two cell types: while T cells will decrease IL-7R expression in response to binding IL-7, ILC do not.

Future studies will attempt to explain the biological significance of these two distinct cell types competing for a shared source of survival stimuli.

In addition to Martin, Kim and Surh, other authors of the study, “Interleukin-7 Availability Is Maintained by a Hematopoeitic Cytokine Sink Comprising Innate Lymphoid Cells and T cells,” were Drs. Darina Spasova and Kwesi Frimpong-Boateng, both graduates of the Kellogg School of Science and Technology

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see www.scripps.edu.

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