The development of autoimmunity in C57BL/6 lpr mice correlates with the disappearance of natural killer type 1-positive cells: evidence for their suppressive action on bone marrow stem cell proliferation B cell immunoglobulin secretion and autoimmune symptoms

摘要

F1 hybrid mice are able to acutely reject parental marrow grafts, a phenomenon that is due to natural killer type 1-positive (NK1+) cells. Circumstantial evidence had suggested that the antigenic determinants recognized by these cells are self-antigens, leading to the hypothesis that the physiological role of NK1+ cells is a downregulatory or suppressive function on bone marrow stem cell proliferation and lymphocyte function. In analyzing this hypothesis it is shown here that in young mice there is a temporal correlation between appearance of NK1+ cells in the spleen and the ability to reject allogeneic marrow or to suppress endogenous stem cell proliferation. The reverse situation exists in mice expressing the homozygous lpr gene. Whereas in young mice cells with NK1+ phenotype are demonstrable, these cells disappear with age, i.e., at the time autoimmunity develops. Concomitant with the disappearance of NK1+ cells, the ability to reject marrow grafts and to control endogenous stem cell proliferation also vanishes. The suggestion that the development of autoimmunity is causally related to the disappearance of NK1+ cells is supported by experiments in which NK1+ cells were either eliminated by antibody injection or increased by adoptively transferring cell populations enriched for NK1+ cells into lpr mice. It is shown that removal of cells enhances autoimmunity, whereas injection of NK1+ cells delays the onset of autoimmunity. In vitro assays are presented that demonstrate that suppression of autoantibody-secreting B cells is due to two NK1+ cell populations, one that expresses CD3 and causes specific suppression and one that lacks CD3 and causes nonspecific suppression.