Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes.
BACKGROUND
Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes.


METHODS
We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population.


RESULTS
We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls.


CONCLUSIONS
In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
Gattazzo
Cristina
C
Department of Clinical and Experimental Medicine, University of Padova, via Giustiniani 2, Padua, Italy.
Teramo
Antonella
A
Miorin
Marta
M
Scquizzato
Elisa
E
Cabrelle
Anna
A
Balsamo
Mirna
M
Agostini
Carlo
C
Vendrame
Elena
E
Facco
Monica
M
Albergoni
Maria Paola
MP
Trentin
Livio
L
Vitale
Massimo
M
Semenzato
Gianpietro
G
Zambello
Renato
R
D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000473:pathology*; D054066:Leukemia, Large Granular Lymphocytic / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D054341:Receptors, KIR3DL1 / Q000172:deficiency* / Q000235:genetics; D054349:Receptors, KIR3DS1 / Q000235:genetics
D012333:RNA, Messenger; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1
Oncogene. 2008 Oct 6;27(45):5932-43
18836474
Mol Immunol. 2009 Jun;46(10):2064-70
19394699
PLoS Pathog. 2008 Mar 07;4(3):e1000005
18369464
Blood. 1993 May 1;81(9):2381-5
8481518
Blood. 1993 Jul 1;82(1):1-14
8324214
J Immunol. 2002 Oct 15;169(8):4253-61
12370356
Adv Immunol. 1989;47:187-376
2683611
Trends Immunol. 2001 Nov;22(11):633-40
11698225
Immunogenetics. 2002 Jul;54(4):221-9
12136333
J Immunol. 2007 Jan 1;178(1):235-41
17182560
Leukemia. 1993 Jun;7(6):782-8
8388971
Blood. 1981 Oct;58(4):759-67
7272506
Immunogenetics. 2006 Nov;58(11):865-72
17033821
Immunity. 1997 Dec;7(6):739-51
9430220
Blood. 2004 May 1;103(9):3431-9
14726391
Blood. 1982 Aug;60(2):404-11
7093525
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4778-83
10781084
Eur J Immunol. 1996 Aug;26(8):1816-24
8765026
Leukemia. 1995 Jul;9(7):1207-11
7630196
Annu Rev Immunol. 1996;14:619-48
8717527
Curr Stem Cell Res Ther. 2007 Jan;2(1):39-52
18220891
Microbes Infect. 2002 Dec;4(15):1523-30
12505524
Leuk Res. 2005 Apr;29(4):381-7
15725471
Blood. 1997 Aug 15;90(4):1403-9
9269757
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6948-53
15870198
Immunity. 1997 Dec;7(6):753-63
9430221
Clin Immunol. 2003 Oct;109(1):80-8
14585279
Leukemia. 2007 May;21(5):1060-9
17361229
Annu Rev Immunol. 1999;17:875-904
10358776
Curr Top Microbiol Immunol. 2006;310:13-22
16909904
J Clin Invest. 1989 Jul;84(1):51-5
2544630
Eur J Haematol. 2006 Jan;76(1):23-32
16343268
Fertil Steril. 2007 Jan;87(1):24-32
17081533
Blood. 1997 Jan 1;89(1):256-60
8978299
Hum Immunol. 2004 Jun;65(6):602-12
15219380
Annu Rev Immunol. 2001;19:197-223
11244035
Annu Rev Immunol. 1998;16:359-93
9597134
Nat Genet. 1998 Jul;19(3):219-20
9662389
Genes Dev. 2002 Jan 1;16(1):6-21
11782440
Blood. 1998 Apr 15;91(8):2985-90
9531610
J Exp Med. 2003 Jan 20;197(2):245-55
12538663
Cancer Res. 2000 Feb 15;60(4):1043-8
10706122
Blood. 2003 Sep 1;102(5):1797-805
12750175