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.

Abstract

SummaryF1 hybrid mice are able to acutely reject parental marrow grafts, a phenomenon that is due to natural killer type 1-positive (NKI+) 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 Ipr 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 Ipr 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.

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

“…In a previous study, adoptive transfer of NK1.1-enriched (NK1.1 + CD3 + and NK1.1 + CD3 -) cells reduced the number of CD3 + B220 + cells in C57BL/6-lpr mice [16]. This regulatory effect of NK1.1-expressing cells is probably conferred by CD1d-reactive NKT cells, since CD1d KO MRLlpr mice have an increased TCR § g + B220 + cell population (Fig.…”

“…In fact, MRL-lpr mice exhibit a selective reduction in the numbers and functions of invariant (V § 14J § 18) NKT cells before the onset of clinical disease [14]. Other studies have also found a specific decrease in the expression of invariant V § 14 TCR mRNA by NKT cells before the onset of disease in MRLlpr mice [15] and in the numbers of NK1.1-expressing cells in C57BL/6-lpr mice [16]. Consistent with a protective role of CD1d-reactive T cells, patients with SLE also have a selective reduction of NKT cells [17][18][19].…”

“…The role of NK1.1 + cells, which include NK cells, classical NKT cells and small subsets of other cell types that express this marker, in the development of autoantibodies in C57BL/6-lpr mice has been investigated [16]. These studies showed that: (a) NK1.…”

NK3-Like NK Cells Are Involved in Protective Effect of Polyinosinic-Polycytidylic Acid on Type 1 Diabetes in Nonobese Diabetic Mice

“…The protective or disease-promoting effects of NK cells are dependent on disease model. In patients with multiple sclerosis and lpr mice, which display a phenotype that resembles that of patients with systemic lupus erythematosus, NK cells play a protective role (17,18). In EAE models, the role of NK cells is controversial, similar to diabetes.…”

Dissociation of the Genetic Loci Leading to B1a and NKT Cell Expansions from Autoantibody Production and Renal Disease in B6 Mice with an Introgressed New Zealand Black Chromosome 4 Interval

“…The role of NKT cells in lupus is controversial (45,(53)(54)(55)(56)(57)(58). A reduced level of NKT cells is observed at the spontaneous onset of lupus in the MRL/lpr mouse strain and elimination of NK1.1 cells or the CD1d gene exacerbated disease progression.…”