Development of human T and natural killer cells

ELLS BELONGING to the lymphoid lineages are instrumental in protecting their hosts against an enormous diversity of foreign agents. Of these, T and B cells are most extensively studied. The way these cells recognize foreign antigens through the T-cell receptor (TCR) and Igs is now well understood. These receptors are generated by gene rearrangements, providing T and B cells with an almost unlimited capacity to recognize potential pathogens. Several mechanisms exist to ensure that T and B cells stay indifferent towards self antigens and insight into how this is achieved is increasing. Cells belonging to the third lymphoid lineage, natural killer (NK) cells, are able to kill a wide variety of target cells, including tumor cells and cells infected with bacteria and viruses. The physiologic role of these cells is not fully understood, but it is generally believed that these cells form a first line of defense towards infections by cytolytic activity or the secretion of certain cytokines. NK cells do not possess rearranged receptor genes, but recent work has established that NK cells do have the capacity to recognize major histocompatibility complex (MHC) class I antigens in vitro and in vivo.' However, in contrast to T cells that are generally activated by the interaction between MHC/ peptide complexes and TCR, NK cells are turned off by interaction of their specific receptors with MHC class I antigens. The developmental relationship of the three lymphoid lineages is not precisely known. Like all hematopoietic cells, the lymphoid lineages are derived from pluripotent stem cells, operationally defined not only by their capacity to give rise to blood cells but also to self-renew. A popular model of lymphoid differentiation postulates that when stem cells differentiate to mature lymphoid cells they pass through a common lymphoid progenitor cell. This still elusive cell type should be committed to the lymphoid lineages and should have lost the capacity to differentiate into any of the other hematopoietic cell lineages. Evidence for a separate regulation of lymphoid and myeloiderythroid development is provided by the observation that mice functionally deficient for the transcription factor Ikaros have myeloid and erythroid cells but lack T, B, and NK cek2 However, there is some evidence from studies with hematopoietic tumors that preB cells have not completely lost their capacity to develop into myeloid cells.3 As an alternative to the idea of a fixed sequence of branchpoints involving irreversible differentia