Work

Telomerase Activity in Regulatory T Cells is Inversely Associated With Severity of Chronic Graft-Versus-Host Disease (cGVHD) After Hematopoietic Stem Cell Transplantation (HSCT)

Year: 2011

Type: article

Abstract: CD4+CD25+Foxp3+ regulatory T cells (Treg) play an important role in the maintenance of peripheral tolerance and control of chronic graft versus host disease (cGVHD). Previous studies have shown that Treg undergo extensive homeostatic proliferation after allogeneic HSCT. However, Treg are also susceptible to apoptosis, and the inability to maintain survival of rapidly proliferating Treg may contribute to the development of cGVHD. Telomeres play an important role in cell senescence and we examined whether telomerase activity and telomere length were associated with Treg homeostasis after allogeneic HSCT and cGVHD. We examined Treg and conventional CD4 T cells (Tcon) in 52 patients with hematologic malignancies who survived more than 2 years after HSCT. Tcon and Treg were purified by flow cytometric cell sorting. Relative telomere length was measured by real time PCR. Telomerase activity was measured by PCR-ELISA. Telomere length was significantly shorter in Treg compared to Tcon in all patients (0.10 vs 0.25; p < 0.0001), but Treg telomere length was not correlated with severity of cGVHD. Treg telomerase activity and Treg number were inversely associated with severity of cGVHD (Treg telomerase activity/Treg cell number/ul, 37/33 in no cGVHD, 34/20 in mild cGVHD, 7/19 in moderate cGVHD, 1.2/8 in severe cGVHD; p < 0.0001, p = 0.01, respectively). Ki-67 expression, a measure of proliferation, was higher in Treg compared with Tcon in all patients (5.7% vs 0.9%; p < 0.0001), and Ki-67 in Treg was inversely associated with severity of cGVHD (p = 0.002). Bcl-2 expression, a measure of susceptibility to apoptosis, in Treg was also inversely associated with severity of cGVHD (p = 0.0009). Finally, there was a significant correlation between Treg telomerase activity and Bcl-2 expression (r = 0.69, p < 0.0001), suggesting that high telomerase activity is associated with other mechanisms that promote survival of Treg. These data indicate that activation of telomerase in Treg after allogeneic HSCT does not prevent overall telomere shortening. However, telomerase activation increases the replicative life span of Treg by protecting them from apoptosis. Failure to activate telomerase in Treg restricts their proliferative capacity and also appears to increase apoptotic susceptibility, resulting in the loss of peripheral tolerance and the development of severe cGVHD.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2010.12.514