Tumor Necrosis Factor Promotes Human T‐Cell Development in Nonobese Diabetic/Severe Combined Immunodeficient Mice

Abstract

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.