Interleukin-21: an interleukin-2 dependent player in rejection processes.
BACKGROUND
Interleukin (IL)-21 is the most recently described cytokine that signals via the common cytokine receptor (gammac), is produced by activated CD4+ T-cells, and regulates expansion and effector function of CD8+ T-cells.


METHODS
To explore the actions of IL-21 with other gammac-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R alpha-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions. Additionally, IL-21 and IL-21R alpha-chain expression was studied in biopsies of heart transplant patients.


RESULTS
Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R alpha-chain. Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R alpha-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated. IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21. Blockade of the IL-21 route by anti-IL-21R alpha-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells. Also, in vivo alloreactivity was associated with IL-21/IL-21R alpha-chain expression. After heart transplantation, the highest intragraft IL-21, IL-21R alpha-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.001, P=0.01, P=0.03).


CONCLUSIONS
IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.
Baan
Carla C
CC
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands. c.c.baan@erasmusmc.nl
Balk
Aggie H M M
AH
Dijke
I Esmé
IE
Korevaar
Sander S
SS
Peeters
Annemiek M A
AM
de Kuiper
Ronella P
RP
Klepper
Mariska
M
Zondervan
Pieter E
PE
Maat
Lex A P W M
LA
Weimar
Willem
W
D049109:Cell Proliferation; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic; D004699:Endocardium / Q000378:metabolism; D006084:Graft Rejection / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D009206:Myocardium / Q000378:metabolism; D011184:Postoperative Period; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D000098546:Interleukin-21
D007376:Interleukin-2; D007378:Interleukins; D020033:Protein Isoforms; D012333:RNA, Messenger; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21