ABSTRACT
Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.
Subject(s)
BH3 Interacting Domain Death Agonist Protein/immunology , Interleukin-15/immunology , Leukemia, Large Granular Lymphocytic/immunology , Lymphocytes/immunology , Proteasome Endopeptidase Complex/metabolism , Animals , BH3 Interacting Domain Death Agonist Protein/biosynthesis , BH3 Interacting Domain Death Agonist Protein/deficiency , BH3 Interacting Domain Death Agonist Protein/metabolism , Humans , Interleukin-15/deficiency , Interleukin-15/metabolism , Interleukin-15/pharmacology , Interleukin-2/immunology , Interleukin-2/metabolism , Killer Cells, Natural/immunology , Leukemia, Large Granular Lymphocytic/enzymology , Leukemia, Large Granular Lymphocytic/metabolism , Lymphocytes/enzymology , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proteasome Inhibitors , Proto-Oncogene Proteins c-mdm2/immunology , Proto-Oncogene Proteins c-mdm2/metabolismABSTRACT
Innate immune responses provide the host with its first line of defense against infections. Signals generated by subsets of lymphocytes, including NK cells, NKT cells, and APC during this early host response determine the nature of downstream adaptive immune responses. In the present study, we have examined the role of innate NK cells in an autoimmune model through the use of primary immunization with the myelin oligodendrocyte glycoprotein peptide to induce experimental autoimmune encephalomyelitis (EAE). Our studies have shown that in vivo depletion of NK cells can affect the adaptive immune responses, because NK cells were found to regulate the degree of clinical paralysis and to alter immune adaptive responses to the myelin oligodendrocyte glycoprotein peptide. The requirement for NK cells was reflected by changes in the T cell responses and diminished clinical disease seen in mice treated with anti-NK1.1, anti-asialo GM1, and selected Ly49 subtype-depleted mice. In addition to alteration in T cell responses, the maturational status of dendritic cells in lymph nodes was altered both quantitatively and qualitatively. Finally, examination of TCR Vbeta usage of the brain lymphocytes from EAE mice indicated a spectra-type change in receptor expression in NK- depleted mice as compared with non-NK-depleted EAE mice. These findings further establish a recently postulated link between NK cells and the generation of autoreactive T cells.
