Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells.
Previously, we have shown that IL-21R(-/-) splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R(-/-) splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL-21R(-/-) splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R(-/-) and wild-type cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 × 10(5) and 5 × 10(6) with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R(-/-) cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R(-/-) bulk splenocytes results from cooperative compensation by CD8 T-cells.
Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi, Japan.
A
A
Meguro
K
K
Ozaki
K
K
Hatanaka
I
I
Oh
K
K
Sudo
T
T
Ohmori
H
H
Matsu
R
R
Tatara
K
K
Sato
Y
Y
Sakata
S
S
Nakae
W J
WJ
Leonard
K
K
Ozawa
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000098546:Interleukin-21
C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21
Blood. 2002 Nov 1;100(9):3429-31
12384449
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14028-33
18779574
Cancer Immunol Immunother. 2008 Oct;57(10):1439-49
18286285
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6688-93
16618932
J Clin Oncol. 2008 Apr 20;26(12):2034-9
18347008
Nat Immunol. 2007 Sep;8(9):967-74
17581537
J Clin Invest. 2001 Jun;107(12):1581-9
11413166
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1518-23
19164519
Science. 2002 Nov 22;298(5598):1630-4
12446913
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3921-6
15001702
J Biol Chem. 2002 Aug 16;277(33):29355-8
12072446
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11439-44
11016959
Blood. 2009 Dec 17;114(26):5375-84
19843883
J Immunol. 2007 Jan 15;178(2):838-50
17202345
J Clin Invest. 1999 Aug;104(3):317-25
10430613
Nature. 2007 Jul 26;448(7152):484-487
17581588
J Immunol. 2005 Aug 15;175(4):2167-73
16081783
Nature. 2007 Jul 26;448(7152):480-3
17581589
Nat Med. 2003 Sep;9(9):1144-50
12925844
Diabetes. 2009 May;58(5):1144-55
19208913
J Immunol. 2010 Aug 1;185(3):1920-6
20574002
Biol Blood Marrow Transplant. 2003 Sep;9(9):592-603
14506661
J Leukoc Biol. 2008 Aug;84(2):348-56
18467657
Nature. 2000 Nov 2;408(6808):57-63
11081504
J Immunol. 2004 Nov 1;173(9):5361-71
15494482
Blood. 2002 Jun 1;99(11):4207-15
12010827
Clin Cancer Res. 2007 Jun 15;13(12):3630-6
17575227
Clin Cancer Res. 2009 Mar 15;15(6):2123-9
19276257
Bone Marrow Transplant. 2010 Apr;45(4):723-9
19718060
Blood. 2008 Jun 1;111(11):5326-33
18276844
Nat Rev Immunol. 2005 Sep;5(9):688-98
16138102
Cancer Res. 2003 Dec 15;63(24):9016-22
14695220