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Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital of Los Angeles, Los Angeles, CA 90027
The beige/nude/xid/human (bnx/hu) model of human hematopoiesis
provides a unique opportunity to study extrathymic human T lymphocyte
development in an in vivo system. Purified human hematopoietic stem
cells develop into mature T lymphocytes and immature progenitors in the
bone marrow of athymic bnx mice. The human T cells are all
TCR
+ and display a restricted TCRV repertoire. In
the current studies, we examined the effects of systemic human IL-7
(huIL-7) administration on the phenotype and the activation status of
the bnx/hu T cells. In the majority of the mice that did not have
huIL-7 administration, a higher frequency of human
CD3+/CD8+ than
CD3+/CD4+ T cells developed in the bone marrow.
This phenomenon is also frequently observed in human bone marrow
transplant recipients. Extremely low levels of IL-2 were expressed by
human CD3+ cells isolated from these mice, in response to
PMA plus ionomycin and to CD3 and CD28 cross-linking. IL-4 was not
expressed by cells exposed to either stimulus, demonstrating a profound
inability of the bnx/hu T cells to produce this cytokine. Systemic
production of huIL-7 from engineered stromal cells transplanted into
the mice increased the human CD4 to CD8 ratios, and increased the ratio
of memory to naive CD4+ and CD8+ T cells. The
human CD3+ cells recovered from mice that had systemic
huIL-7 and equivalent numbers of CD3+/CD4+ and
CD3+/CD8+ cells in the marrow were still unable
to produce IL-4 in response to any condition tested, but were capable
of normal levels of IL-2 production following
stimulation.
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