RERF Report No. 7-13

Paper published in The Journal of Immunology§“Linkage between Dendritic and T-cell Commitments in Human Circulating
Hematopoietic Progenitors”
Seishi Kyoizumi, Yoshiko Kubo, Junko Kajimura, Kengo Yoshida, Tomonori Hayashi, Kei Nakachi,
Lauren F. Young, Malcolm A. Moore, Marcel R.M. van den Brink, Yoichiro Kusunoki
J Immunol 2014 (June); 192(12):5749–60(doi: 10.4049/jimmunol.1303260)

Study Findings
Dendritic cells (DCs) play an indispensable role in the differentiation and functional expressionof T cells. These two types of cells differentiate from hematopoietic stem cells (HSCs), and the current
study finds that the frequencies of T-cell and DC precursors are significantly linked with each other instem cells existing in blood, whereas they are not linked to the precursor frequency (PF) of naturalkiller (NK) cells.
Explanation
1. Objectives
DCs are a type of leukocyte with dendrites. They initiate an adaptive immune response byconveying antigen information about viruses and bacteria that have invaded the body to T cells, which
serve as a ‘control tower’ for the adaptive immune response. DCs also prevent the generation ofself-antigen-responsive T cells in the thymus as a negative selection. Because self-antigen-responsive
T cells recognize substances that make up their host body as antigens, these cells are detrimental. DCs
are thus essential for the differentiation and functional expression of T cells. Based on thisunderstanding, we hypothesized that there may be a correlation between the potency of HSCs todifferentiate into DCs and their potency to differentiate into T cells, suggesting a linkage between DCand T-cell commitments. (HSCs are the least differentiated cells that can give rise to all blood celltypes, are long lived, and have the ability to self-replicate.) Verifying this hypothesis was considered toprovide important findings for ongoing studies of A-bomb survivors involving T-cell progenitors andDCs. DCs can be classified as conventional DCs (cDCs, which inform T cells of antigens to initiate
direct attack) or plasmacytoid DCs (pDCs, which produce type-I interferon and induce anti-viral
infection immunity). In the present study, we analyzed DC progenitors of both types.
2. Methods
It is possible to separate hematopoietic progenitor cells (HPCs, cells with the potency todifferentiate into T cells and DCs) in human peripheral blood using a cell sorter, and then todifferentiate HPCs into T cells and NK cells using the culture method reported in Kyoizumi et al.: JImmunol 2013; 190:6164–72. NK cells are a type of cytotoxic lymphocyte that is important for theinnate immune system. Since the present study confirmed that this culture method could induce
differentiation of HPCs into DCs, we used it as an experimental system to simultaneously assay T cells,
NK cells, and DC progenitors. Blood samples were collected, based on informed consent, from 20
RERF in-house volunteer donors aged 26–65 years, and we measured the PFs of T cells and NK cells,
as well as cDCs and pDCs, based on the culture method, to examine correlations among the PFs ofthese cells. Furthermore, we examined the potencies of single precursor cells to differentiate into Tcells and NK cells, as well as cDCs and pDCs, based on precursor cell clonal culture.
3. Results(1) The PFs of cDCs and pDCs in HPCs were found to correlate significantly with T-cell PFs, but notwith NK-cell PFs.
(2) The precursors producing T cells and NK cells were classified into clones producing T/NK dual-,
T single-, and NK single-lineage precursors. The clones of T/NK dual- and T single-lineage
precursors produced cDCs or pDCs at high frequencies. The clones of NK single-lineage
precursors, however, produced very few cDCs or pDCs.
1RERF Report No. 7-13

4. Consideration and Conclusion
These findings show that T-cell and DC commitments are linked with each other, as indicatedwith the green lines below. On the other hand, this research suggests that NK-cell commitment isinduced independently from DC commitment. In addition, the linkage between T-cell and DC
precursors might be intrinsically imprinted in long-lived HSCs existing in bone marrow that areself-replicating, since the T-cell and DC progenitors in the human body have short life spans.
Note: Progenitors are specific cells, generated from stem cells, that are able to differentiate into more
specific types of cells.

Long-lived HSC

T/NK
dual-lineage
precursor

T/NK/DC duallineage precursor

NK cell

T cellT/DC commitment
NK commitment

cDCDC
pDC

The Radiation Effects Research Foundation has studied A-bomb survivors and their offspring in Hiroshima
and Nagasaki for more than 60 years. RERF’s research achievements are considered the principal scientific basis
for radiation risk assessment by the United Nations Scientific Committee on the Effects of Atomic Radiation(UNSCEAR) and for recommendations regarding radiation protection standards by the International
Commission on Radiological Protection (ICRP). RERF expresses its profound gratitude to the A-bomb survivors
and survivors’ offspring for their cooperation in our studies.
§The Journal of Immunology is an international review journal published by the American Association ofImmunologists. The journal publishes findings from all areas of experimental immunology, including innate andadaptive immunity, inflammation, host defense, clinical immunity, and autoimmunity. (Impact factor in 2012:5.52)

2