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.