Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α-TNF Receptor-2 Pathway

Acute myeloid leukemia (AML) harbors an immune suppression environment, featured by increased regulatory T cells (Tregs). The expression of tumor necrosis factor receptor-2 (TNFR2) on Tregs could be used to identify the maximally suppressive Treg population, and INF-alpha furtherly promoted the expansion and function of Tregs via TNFR2 in mice. However, the role of TNF-alpha has not been determined in AML patients. In view of high levels of INF-alpha and Tregs in AML patients, we hypothesized that the increased frequency of Tregs may rely on TNF-alpha TNFR2 pathway. We investigated the levels of INFR2(+) Tregs and INF-alpha secreted by T cells in peripheral blood (PB) of AML by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our results showed the elevated plasma INF-a in PB of newly diagnosed (ND) AML patients. The production of TNF-alpha by CD4(+) T cells, especially by T helper (Th)17 cells was remarkably higher in ND AML patients than in complete remission (CR) patients and healthy controls. Then, we found that the circulating frequencies of CD4(+)CD25(+) Tregs and CD4(+)CD25(high) Tregs in AML patients were elevated compared with those in healthy controls and CR patients. TNFR2 expression was much higher on Tregs in AML patients and was preferentially expressed on CD4(+)CD25(high) T cells. Furthermore, we confirmed that, in vitro, the additional INF-alpha can increase the frequency of Tregs through TNFR2 in both AML patients and healthy controls. Summarily, in AML patients, the abnormally elevated level of INF-alpha secreted by CD4(+) T especially Th17 cells promoted the higher Tregs frequency via the INF-alpha TNFR2 pathway.