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T-cell lineage commitment and cytokine responses of thymic progenitors
TA Moore and A Zlotnik
Immunology Department, DNAX Research Institute of Molecular and Cellular
Biology, Palo Alto, CA 94304-1104, USA.
The earliest steps of intrathymic differentiation recently have been
elucidated. It has been reported that both CD4lo (CD44+ CD25- c-kit+ CD3-
CD4lo CD8-) and pro-T cells (CD44+ CD25+ c-kit+ CD3- CD4- CD8-,
representing the next step in maturation) exhibit germline T-cell receptor
beta and gamma loci, suggesting that neither population is exclusively
committed to the T-cell lineage. Several groups have shown that CD4lo cells
retain the capacity to generate multiple lymphoid lineages in vivo;
however, the lineage commitment status of pro-T cells is unknown. To
determine when T-cell lineage commitment occurs, we examined the ability of
sorted CD4lo and pro-T cells to generate lymphoid lineage cells in vivo or
in fetal thymic organ cultures (FTOCs). When intravenously injected into
scid mice, CD4lo cells generated both T and B cells, whereas the progeny of
pro-T cells contained T cells exclusively. Fetal thymic organ cultures
repopulated with CD4lo cells contained both T and natural killer (NK)
cells, whereas cultures repopulated with pro-T cells contained T cells
almost exclusively. These observations strongly suggest that T-cell lineage
commitment occurs during the transition of CD4lo to pro-T cells. Because it
is likely that the thymic microenvironment plays a critical role in T-cell
commitment, we compared the responses of CD4lo and pro-T cells to various
cytokine combinations in vitro, as well as the ability of the cultured
cells to repopulate organ cultures. Cytokine combinations that maintained
T-cell repopulation potential for both CD4lo and pro-T cells were found.
CD4lo cells proliferated best in response to the combination containing
interleukin-1 (IL-1), IL-3, IL- 6, IL-7, and stem cell factor (SCF). Unlike
CD4lo cells, pro-T cells were much more dependent upon IL-7 for
proliferation and FTOC repopulation. However, combinations of cytokines
lacking IL-7 were found that maintained the T-cell repopulating potential
of pro-T cells, suggesting that, whereas this cytokine is clearly very
important for normal pro-T cell function, it is not an absolute necessity
during early T-cell expansion and differentiation.
Volume 86,
Issue 5,
pp. 1850-1860,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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