IL-7 enhances the responsiveness of human T cells that develop in the bone marrow of athymic mice.
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 alpha beta(+) and display a restricted TCRV beta 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.
Tsark
E C
EC
Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital of Los Angeles, Los Angeles, CA 90027, USA.
Dao
M A
MA
Wang
X
X
Weinberg
K
K
Nolta
J A
JA
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D015851:Interleukin-7 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude / Q000235:genetics* / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera / Q000276:immunology
D000276:Adjuvants, Immunologic; D015704:CD4 Antigens; D016827:CD8 Antigens; D006684:HLA-DR Antigens; D007376:Interleukin-2; D015851:Interleukin-7; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D017493:Leukocyte Common Antigens