Decreased Telomerase Activity In CD4 Regulatory T Cells Is Associated with Severity of Chronic Graft-Versus-Host Disease (cGVHD) After Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Kawano Yutaka , Kim Haesook , Matsuoka Ken-ichi , Lazo-Kallanian Suzan , Daley John , Antin Joseph H. , Soiffer Robert , Ritz Jerome 
Published: October 2019

Abstract

Abstract 1257
CD4+CD25+Foxp3+ regulatory T cells (Treg) are known to play an important role in the maintenance of peripheral tolerance and control of cGVHD. Recent studies have shown that Treg undergo extensive homeostatic proliferation after allogeneic HSCT. However, highly proliferating Treg are also susceptible to apoptosis and the inability to maintain adequate Treg survival may contribute to the development of cGVHD. Thus, mechanisms of Treg survival and persistence are of great importance. Telomeres are repetitive DNA sequences, located at the ends of each chromosome. Telomeres gradually shorten with each cell division and eventually lead to cell senescence and death. In rapidly dividing cells, telomere length is maintained by telomerase, a reverse transcriptase that prevents premature senescence. Previous studies have shown that abnormal telomerase activity is found in T cells from patients with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, suggesting that telomerase may play a role in the maintenance of immune tolerance. In the present study, we examined whether telomerase activity and telomere length were associated with Treg homeostasis after allogeneic HSCT, particularly in the context of cGVHD. We examined Treg and conventional CD4 T cells (Tcon) in 35 patients with hematologic malignancies (median age 54 yr) who survived without relapse for more than 2 years after HSCT. Patient samples were obtained at 43 months (median, range: 25–99 months) after HSCT. The severity of cGVHD was classified according to NIH criteria. At the time of analysis, 2 patients had no cGVHD, 19 had mild cGVHD, 9 had moderate cGVHD, and 5 had severe cGVHD. CD4+CD25-CD127+ Tcon and CD4+CD25+CD127- Treg were isolated 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 (0.05 vs 0.28; p<0.01), but there was no correlation between telomere length and severity of cGVHD (see Table below) in both Treg and Tcon. Telomerase activity was increased in Treg compared to Tcon (29.73 vs 8.95; p<0.01). In contrast to telomere length, telomerase activity of Treg is significantly associated with severity of cGVHD (38.89 in patients with no or mild cGVHD vs. 8.19 in patients with moderate or severe GVHD, p=0.0002). These data indicate that induction of telomerase activity in Treg after allogeneic HSCT does not prevent overall telomere shortening. However, activation of telomerase appears to increase the replicative life span of Treg and provides a mechanism for maintaining survival of these cells in vivo. In contrast, failure to activate telomerase in some patients may lead to shortened survival of Treg, inability to maintain peripheral tolerance and development of severe cGVHD.

Disclosures:
No relevant conflicts of interest to declare.