Patients with Early-Stage Myelodysplastic Syndromes Show Increased Frequency of CD4+CD25^high+CD127^low Regulatory T Cells

Abstract

Regulatory T cells (T_reg) have often been ascribed a role in the pathophysiology of several neoplastic diseases considering their potential ability to suppress anti-tumor immunity. This is particularly the case in myelodysplastic syndromes (MDS), which are clonal hematologic disorders characterized by marked immune dysregulation. We analyzed T_reg frequencies in a cohort of 36 patients with early-stage MDS using a flow-cytometric approach based on the concomitant expression of CD25 and CD127. MDS patients showed a higher frequency of CD4+CD25^high+CD127^low T_reg than healthy controls (1.51 vs. 1.14%), with no specific effect of patient- and disease-related factors. Our data point to impaired anti-tumor immunity in patients with MDS, even in the early stage, which has already been noted in other clonal disorders.

Azacitidine improves the T-cell repertoire in patients with myelodysplastic syndromes and acute myeloid leukemia with multilineage dysplasia

“…On the other hand, a registry study focusing on the risk of developing myeloid malignancies in patients with different autoimmune diseases, reported an increased risk of developing MDS, particularly high in autoimmune hemolytic anemia and polyarteritis nodosa [26]. Lastly over the last few years different cell subsets characterized by specific immune functions, including Treg [3,4,27], natural killer cells [28], CD3+ CD4+ IL-17 producing T-cells (Th17) [29] and even CD4+ CD8+ double-positive T-cells [30], have been demonstrated to be potentially involved in the MDS evolution.…”

“…We also investigated the frequency of regulatory T-cells, by considering the CD4+ cell fraction characterized by a very high surface expression (>2 log) of CD25 and by a very low expression of CD127 (<2 log) [4]. In all subjects this cell fraction was then confirmed to be >95% positive for cytoplasmic FoxP3 and CD152 (all antibodies from Becton Dickinson, San Jose, CA).…”

“…Even though several studies have pointed to a crucial role for genetic lesions specifically involving the stem cell compartment [1], clinical and laboratory findings suggest that a marked dysregulation within the immune system may play a central role in their evolution. Indeed, beside the occurrence of autoimmune manifestations such as glomerulonephritis, vasculitis and interstitial pneumonitis in about 10% of MDS patients [2], CD4+Foxp3+ regulatory T cells (Treg) are often expanded [3,4]. In addition, in vitro studies showed that patient T-cells can be directly responsible for the functional inhibition of hematopoietic precursors [5].…”

Current therapy of myelodysplastic syndromes

“…Second, marked aberrations in the humoral and cellular elements of both arms of the immune system, the innate and the adaptive, have been documented in patients with MDS. In early stage MDS, increased pro-inflammatory cytokines such as TNF-alpha and interferon-gamma, increased frequency of CD4+CD25 high + CD127 low + regulatory T-cells, and skewing of the T-cell receptor V-beta repertoire due to selective oligoclonal expansion in cytotoxic CD8+ T-cells have been observed [93–96]. In some subsets of MDS, the selective proliferation of both helper CD4+ T-cells (mostly polyclonal) and cytotoxic CD8+ T-cells (mostly oligoclonal) is believed to underlie an autoimmune attack against the dysplastic hematopoietic progenitors [93].…”

Autoimmunity and Inflammation in Myelodysplastic Syndromes

“…On the other hand, increased T reg activity can promote tumorigenesis through loss of immunosurveillance [40]. In MDS, patients with advanced disease demonstrate increased T regs that correlate with poor outcome, while lower-risk patients have decreased T regs [41,42,43,44,45]. Furthermore, low-marrow T regs are associated with both an increase in the CD8+ T-cell compartment in the marrow [41] and recruitment of proinflammatory IL-17-producing T-helper cells (TH17) [46].…”