Inadequate immune regulatory function of CD4+CD25bright+FoxP3+ T cells in heart transplant patients who experience acute cellular rejection.

Background. CD4 + CD2S bright+ FoxP3 + 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 CD4 + CD25 bright+ FoxF3 + 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 CD4 + CD25 bright+ T cells and of FoxF3 + cells within this population was comparable. Yet, CD4 + CD25 bright+ FoxP3 + T cells of rejectors had a higher CD127 expression than those of nonrejectors (P<0.0001). Depletion of CD4 + CD25 bright+ 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 CD4 + CD25 bright+ T cells only suppressed the overall antidonor proliferative response of CD25 neg/dim 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 CD4 + CD25 bright + T cells of rejectors already had a lower suppressive capacity than those of nonrejectors before transplantation (P=0.04). Conclusion. CD4 + CD25 bright+ FoxP3 + 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 CD4 + CD25 bright+ FoxF3 + regulatory T cells may be pivotal for the prevention of acute cellular rejection after clinical heart transplantation.