Inadequate immune regulatory function of CD4+CD25bright+FoxP3+ T cells in heart transplant patients who experience acute cellular rejection.
BACKGROUND
CD4CD25FoxP3 regulatory T cells are suppressors of antigen-activated immune reactivity. Here, we assessed the clinically relevant role of these cells in the control of immune responses directed to a transplanted heart.


METHODS
We investigated the phenotype and function of peripheral CD4CD25FoxP3 T cells in heart transplant patients free from acute rejections (n=9) and in rejectors (n=12) before and during acute cellular rejection.


RESULTS
Between rejectors and nonrejectors, the proportion of CD4CD25 T cells and of FoxP3 cells within this population was comparable. Yet, CD4CD25FoxP3 T cells of rejectors had a higher CD127 expression than those of nonrejectors (P<0.0001). Depletion of CD4CD25 T cells from peripheral blood mononuclear cells increased the antidonor proliferative response of both nonrejectors (P=0.0005) and rejectors (P=0.03). In rejectors, however, only a 2-fold increase was measured, whereas the nonrejectors' response became 14 times higher (P=0.002). Reconstitution of CD4CD25 T cells only suppressed the overall antidonor proliferative response of CD25 responder cells of nonrejectors significantly (P=0.001). Moreover, the percentage inhibition of the response was higher in nonrejectors than in rejectors (P=0.02). Analyses of pretransplant samples revealed that CD4CD25 T cells of rejectors already had a lower suppressive capacity than those of nonrejectors before transplantation (P=0.04).


CONCLUSIONS
CD4CD25FoxP3 T cells of heart transplant patients who experience acute rejection had an up-regulated CD127 expression and an inadequate regulatory function compared with those of nonrejecting patients. Our observations suggest that the function of circulating CD4CD25FoxP3 regulatory T cells may be pivotal for the prevention of acute cellular rejection after clinical heart transplantation.
Dijke
I Esmé
IE
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands. i.dijke@erasmusmc.nl
Korevaar
Sander S
SS
Caliskan
Kadir
K
Balk
Aggie H M M
AH
Maat
Alex P W M
AP
Weimar
Willem
W
Baan
Carla C
CC
D000208:Acute Disease; D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit