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Newly described type of immune cell and T cells share similar path to maturity

Better understanding of cells' development has implications in study of inflammatory diseases

Labs around the world, and a core group at Penn, have been studying recently described populations of immune cells called innate lymphoid cells (ILCs). Some researchers liken them to foot soldiers that protect boundary tissues such as the skin, the lining of the lung, and the lining of the gut from microbial onslaught. They also have shown they play a role in inflammatory disease, when the body's immune system is too active.

In animal studies, group-2 innate lymphoid cells (ILC2s) confer immunity during a parasitic infection in mice and are also involved in allergic airway inflammation. A team of Perelman School of Medicine, researchers from the Departments of Medicine, Microbiology, Pathology and Laboratory Medicine, and Cancer Biology, found that maturation of ILC2s requires T-cell factor 1 (TCF-1, the product of the Tcf7 gene) to move forward. TCF-1 is protein that binds to specific parts of DNA to control transcription of genetic information from DNA to messenger RNA.

Avinash Bhandoola, PhD, professor of Pathology and Laboratory Medicine, and Qi Yang, PhD, a postdoc in the Bhandoola lab, describe in Immunity that one mechanism used to build ILCs is the same as that in T cells. Both cell types use a protein pathway centered on Notch that the lab of coauthor Warren Pear, MD, PhD, also in the Pathology and Laboratory Medicine, has studied for the last two decades. Other contributing authors are from the laboratory of David Artis, PhD in Microbiology, that are experts in ILC function, and Angela Haczku, MD, PhD, in the Department of Medicine, who focuses on asthma.

But what makes ILCs and T cells different in their final development? T cells are made in the thymus. ILCs don't need the thymus, but researchers don't know exactly where they are produced, just that the thymus isn't essential for their normal development, unlike T cells.

In the Immunity study, mice without the Tcf7 gene also lack ILC2, and were unable to mount an ILC2 immune response. Forced expression of TCF-1 in bone marrow progenitor cells in the mice partially bypassed the requirement for Notch signaling in the generation of ILC2 in the mice. The researchers suggest that transcription factors such as TCF-1 that underlie early steps of T cell development are also implicated in the development of innate lymphoid cells.

The collaborators' next steps are to better understand the basic steps of ILC development and build mouse models to test ILC function. "We want to know where ILCs develop in the body and what progenitor cells give rise to ILCs." says Bhandoola. "If we succeed in constructing mouse models missing different types of ILC, our collaborators can use them to better figure out what these cells do, and perhaps eventually how to control them."

This work was supported by National Institutes of Health Grants AI059621, AI098428, 5T32CA009140-38, T32CA-009140, DP5OD012116, R01AI047833, T32HD007516, 1F31CA165813, AI095466, AI095608, AI097333, and T32-AI007532.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

Karen Kreeger | EurekAlert!
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