PHILADELPHIA – Contrary to the currently accepted model of T-cell development, researchers at the University of Pennsylvania School of Medicine have found that juvenile cells on their way to becoming mature immune cells can develop into either T cells or other blood-cell types versus only being committed to the T-cell path. The findings appear in this week’s issue of Nature, and have implications for better understanding how T-cell leukemias and other disorders arise.
“It is critically important to understand the life history of the T-cell lineage and to define the steps that multipotent progenitor cells take to mature to T cells,” says lead author Jeremiah Bell, PhD, Postdoctoral Fellow in the Department of Laboratory Medicine and Pathology. “Whether you’re trying to understand T-cell immunodeficiencies, T-cell cancers, or other T-cell-related disorders, you first need to know the steps in T-cell development, and the signals acting at each step.”
The life of a T cell, and all other blood cells, begins in the bone marrow as a hematopoietic stem cell (HSC). HSCs have the potential to become all the different types of cells in the blood, including red blood cells, platelets, white blood cells, and all the cells involved in defending the body against pathogens and foreign proteins. The first stage in the process leading to such diversity is for the HSCs to become the precursor cells called multipotent progenitor (MPPs) cells.
The accepted version of what happens next is that there is a fork in the road to becoming a mature blood cell. Each MPP commits to becoming either a precursor of red cells and non-lymphoid white blood cells (called the myeloid pathway) or a precursor of T and B cells (called the lymphoid pathway). The T-cell precursors then go to the thymus, a small organ located under the breastbone, where they are called early thymic progenitors (ETPs).
“If the currently accepted model of T-cell development is correct, then early thymic progenitors, the ETPs, should be able to make T cells, but unable to make myeloid cells,” explains senior author Avinash Bhandoola, PhD, Associate Professor of Pathology and Laboratory Medicine. “Jeremiah instead found that progenitor cells that make it to the thymus have not yet committed to either the myeloid or T-cell pathway.”
In order to determine the potential of ETPs, the team first had to separate ETPs from all the other cells in a mouse thymus. This was accomplished by sorting the cells based on surface tags that are characteristic of the ETP cell type.
Next, single ETP cells were painstakingly placed into culture so that each container received only one cell. “We really wanted to examine single cells,” says Bell. “Otherwise, even if you do see T cells and myeloid cells, you can’t be certain that they all came from the same progenitor cell.” After growing and dividing for several days, the cells from each container were examined, again by surface tags, to see whether T cells or myeloid cells were present.
To the surprise of Bell and Bhandoola, most of the cultures begun with single cells had become a mixture of T cells and myeloid cells. This means that the majority of early thymic progenitor cells do not commit to becoming T cells by the time they get to the thymus. ETP cells retained the ability to become either T cells or myeloid cells.
Since ETPs showed the potential to give rise to myeloid cell types, the team also asked whether some of the myeloid cells in the thymus normally arise from ETPs. The process of T-cell development in the thymus requires progenitor cells to rearrange pieces of DNA. This process of DNA rearrangement is required to build the antigen receptor used by T cells, and permanently marks ETPs. Bell and Bhandoola found that permanent marks of past DNA rearrangements were present in myeloid cells within the thymus, but not in myeloid cells at other sites. This showed that ETPs give rise to myeloid cells in the normal thymus. “It’s very hard to accommodate these data with our old way of thinking about T-cell development,” notes Bhandoola.
“Now, we want to understand how ETPs make the decision to become myeloid cells or T cells within the thymus,” says Bell. “Although our research is focused on basic science, it is relevant to figuring out how T-cell leukemias develop from early progenitor cells.”
“We’re also wondering about the myeloid cells in the thymus that arise from ETPs,” adds Bhandoola. “Are they doing something we need to know about, and what could that be?”
This work was supported by grants from the National Institute of Allergy and Infectious Diseases, the Leukemia and Lymphoma Society, and an Institutional Training Grant from the National Cancer Institute.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
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 $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 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 $373 million awarded in the 2015 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.