Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues.

Abstract

During early fetal development, T cell precursors home from fetal yolk sac and liver to the epithelial thymic rudiment. From cells that initially colonize the thymus arise mature T cells that populate T cell zones of the peripheral lymphoid system. Whereas colonization of the thymus occurs late in the final third of gestation in the mouse, in birds and humans the thymus is colonized by hematopoietic stem cell precursors during the first third of gestation. Using a large series of early human fetal tissues and a panel of monoclonal antibodies that includes markers of early T cells (CD7, CD45), we have studied the immunohistologic location and differentiation capacity of CD45+, CD7+ cells in human fetal tissues. We found that before T cell precursor colonization of the thymus (7-8 wk of gestation), CD7+ cells were present in yolk sac, neck, upper thorax, and fetal liver, and were concentrated in mesenchyme throughout the upper thorax and neck areas. By 9.5 wk of gestation, CD7+ cells were no longer present in upper thorax mesenchyme but rather were localized in the lymphoid thymus and scattered throughout fetal liver. CD7+, CD2-, CD3-, CD8-, CD4-, WT31- cells in thorax and fetal liver, when stimulated for 10-15 d with T cell-conditioned media and rIL-2, expressed CD2, CD3, CD4, CD8, and WT31 markers of the T cell lineage. Moreover, CD7+ cells isolated from fetal liver contained all cells in this tissue capable of forming CFU-T colonies in vitro. These data demonstrate that T cell precursors in early human fetal tissues can be identified using a mAb against the CD7 antigen. Moreover, the localization of CD7+ T cell precursors to fetal upper thorax and neck areas at 7-8.5 wk of fetal gestation provides strong evidence for a developmentally regulated period in man in which T cell precursors migrate to the epithelial thymic rudiment.

Transplantation of hematopoietic stem cells in utero

“…The fist hematopoietic cells begin to appear in the human fetal thymus at eight to nine weeks gestation. The first appearance of single-positive reactive T lymphocytes in the fetal thymus occurs around 13-14 weeks gestation, and these cells appear in the circulation (post-thymic) at 15-16 weeks gestation [60,61]. Therefore, appropriately timed transplantation of pluripotent, immortal HSCs should theoretically result in permanent, multilineage, hematopoietic chimerism without the need for immunosuppression or marrow ablation.…”

Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion.

“…We are currently using B7 + cell transfectants to address this issue further. While a ligand for CD7 has not been identified, CD7 is one of the earliest T cell-specific markers in the thymus (29,30). Its absence has been reported in one case of severe combined immunodeficiency (31), and CD7 mAb crosslinking has been reported to induce changes in intracellular Ca 2+ (15), as well as enhancing T cell proliferation (14).…”

Soluble CD23 (Fc epsilon RII) and interleukin 1 synergistically induce early human thymocyte maturation.

“…Among human thymocytes, CD7 + CD2 -CD3 -CD4 -CD8 -(referred hereafter as CD7') cells represent the earliest identifiable step (2)(3)(4) . In vitro, these precursors were able to acquire mature T cell antigens (3,4), but cellular interactions and cytokines necessary for this process are poorly understood. We have previously reported that enriched populations of B lymphocytes from blood produce factors (3,5) that promote in vitro development of blood-and bone marrow-derived CD7 + CD2 -precursors.…”