Tumor necrosis factor promotes human T-cell development in nonobese diabetic/severe combined immunodeficient mice.
A major problem after clinical hematopoietic stem cell transplantations is poor T-cell reconstitution. Studying the mechanisms underlying this concern is hampered, because experimental transplantation of human stem and progenitor cells into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice usually results in low T-lymphocyte reconstitution. Because tumor necrosis factor alpha (TNFalpha) has been proposed to play a role in T-lineage commitment and differentiation in vitro, we investigated its potential to augment human T-cell development in vivo. Administration of TNF to irradiated NOD/SCID mice before transplantation of human mononuclear cells from either cord blood or adult G-CSF-mobilized peripheral blood (MPBL) led 2-3 weeks after transplantation to the emergence of human immature CD4(+)CD8(+) double-positive T-cells in the bone marrow (BM), spleen, and thymus, and in this organ, the human cells also express CD1a marker. One to 2 weeks later, single-positive CD4(+) and CD8(+) cells expressing heterogenous T-cell receptor alpha beta were detected in all three organs. These cells were also capable of migrating through the blood circulation. Interestingly, human T-cell development in these mice was associated with a significant reduction in immature lymphoid human CD19(+) B cells and natural killer progenitors in the murine BM. The human T cells were mostly derived from the transplanted immature CD34(+) cells. This study demonstrates the potential of TNF to rapidly augment human T lymphopoiesis in vivo and also provides clinically relevant evidence for this process with adult MPBL progenitors.
Samira
Sarit
S
Immunology Department, Weizmann Institute of Science, Rehovot, Israel.
Ferrand
Christophe
C
Peled
Amnon
A
Nagler
Arnon
A
Tovbin
Yosef
Y
Ben-Hur
Herzl
H
Taylor
Naomi
N
Globerson
Amiela
A
Lapidot
Tsvee
T
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D019070:Cell Lineage; D002465:Cell Movement; D017690:Cell Transplantation; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D004247:DNA