Abstract
Recent evidence has demonstrated that regulatory T cells (Treg) were enriched in the tumor sites of patients with B-cell non-Hodgkin lymphoma (NHL). However, the causes of enrichment and suppressive mechanisms need to be further elucidated. Here we demonstrated that CD4+CD25+FoxP3+CD127lo Treg were markedly increased and their phenotypes were different in peripheral blood (PB) as well as bone marrow (BM) from newly diagnosed patients with B-cell NHL compared with those from healthy volunteers (HVs). Involved lymphatic tissues also showed higher frequencies of Treg than benign lymph nodes. Moreover, the frequencies of Treg were significantly higher in involved lymphatic tissues than those from PB as well as BM in the same patients. Suppression mediated by CD4+CD25+ Treg co-cultured with allogeneic CFSE-labeled CD4+CD25− responder cells was also higher in involved lymphatic tissues from B-cell NHL than that mediated by Treg from HVs. In addition, we found that malignant B cells significantly induced FoxP3 expression and regulatory function in CD4+CD25− T cells in vitro. In contrast, normal B cells could not induce the conversion of CD4+CD25− T cells to Treg. We also showed that the PD-1/B7-H1 pathway might play an important role in Treg induction. Taken together, our results suggest that malignant B cells induce the conversion of CD4+CD25− T cells to Treg, which may play a role in the pathogenesis of B-cell NHL and represent a promising therapeutic target.
Highlights
B-cell non-Hodgkin lymphomas (NHL) are common lymphoid malignancies in which malignant B cells arrested at varying stages of differentiation often involve lymph nodes (LNs) and occasionally extranodal tissues
To investigate a possible role of CD4+CD25+forkhead box P3 (FoxP3)+CD127lo Treg in the immune system in B-cell NHL, both peripheral tolerance and the tumor microenvironment, we measured the frequencies of CD4+CD25+FoxP3+CD127lo Treg in peripheral blood (PB), bone marrow (BM) and involved lymphatic tissues from patients with B-cell NHL
We found that FoxP3+ cells were induced from CD4+CD252 T cells isolated from healthy volunteers (HVs) in the presence of malignant B cells, and FoxP3+ cells could not be induced from CD4+CD252 T cells isolated from B
Summary
B-cell non-Hodgkin lymphomas (NHL) are common lymphoid malignancies in which malignant B cells arrested at varying stages of differentiation often involve lymph nodes (LNs) and occasionally extranodal tissues. T cells are usually present in the tumor microenvironment, which commonly include regulatory T cells (Treg) [1], suggesting that Treg may play a role in regulating tumor growth in patients with B-cell NHL. It is becoming clear that tumors may induce immunologic tolerance by promoting the expansion, recruitment and activation of Treg [2]. Treg, which account for about 5% to 10% of peripheral CD4+ T cells in both mice and humans, include naturally occurring CD4+CD25+ Treg as well as peripherally induced CD4+ Treg [3,4]. Helios, a member of the Ikaros family, was reported as a marker to express on the naturally occurring Treg, but not those induced Treg [5]. Sustained high surface expression of CD25, cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and glucocorticoid-induced TNFR-related protein (GITR) expression are features of suppressive Treg [6,7]
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