Regulation of NK1.1 (NKR-P1/CD161) expression during lymphocyte lineage commitment in the fetal mouse

grantor: University of TorontoT and natural killer (NK) lymphocytes are presumed to share a common intrathymic precursor. The development of conventional Ãß T lymphocytes begins within the early fetal thymus, after the colonization of multipotent CD117+ (c-kit) hematopoietic precursors. Irrevocable commitment to the Ãß T lineage is marked by thymus-induced expression of CD25 (IL-2RÃ) and initiation of genomic rearrangements at the T cell receptor ß (TCRß) loci. However, the contribution of the fetal thymic microenvironment in mediating NK lineage commitment and differentiation has remained largely unappreciated. In particular, the development of functional mouse NK cells occurs first within the early fetal thymus. Mature fetal thymic NK cells are characterized by expression of a type II transmembrane C-type lectin receptor, NK1.1 (NKR-P1/CD161), and by lack of expression of CD117 (NK1.1+/CD117 -). Moreover, NK cell differentiation is preceded by a thymus-induced developmental stage (NK1.1+/CD117lo) that marks lineage commitment of multipotent hematopoietic precursors to the T and NK cell fates, with the subsequent loss of B lymphoid potential. Commitment to this T/NK bipotent stage is induced by fetal thymic stroma, but is not thymus-dependent. Indeed, previously-identified CD90+ (Thy-1) fetal blood "prothymocytes", once thought to represent exclusively T lineage-committed precursors, also exhibit NK lineage potential and are phenotypically and functionally identical to fetal thymic NK1.1 +/CD117lo progenitors. Equivalent populations of NK1.1 +/CD90+/CD117lo progenitors are found in the fetal circulation of both normal and athymic nude (nu/nu) mice. These findings indicate that full commitment of circulating hematopoietic precursors to the T lineage occurs after thymus colonization. Interestingly, the NK1.1 antigen expressed by fetal blood cells does not represent the previously-defined NKR-P1C (CD161C) gene product; rather, it represents a novel NK1.1 antigen expressed in certain mouse strains that is encoded by the closely-related NKR-P1B (CD161B) gene. In contrast to NKR-P1C, which transduces, activating signals by recruiting protein tyrosine kinases, NKR-P1B transduces inhibitory signals by associating with the protein tyrosine phosphatase, SHP-1. Thus, "the NK1.1 antigen" actually represents two distinct gene products possessing opposite regulatory functions. These findings suggest a potential role for NKR-P1 molecules in mediating self/nonself recognition in the immune system.Ph.D