Abstract
Regulatory T cells (Tregs) have a fundamental function in monitoring the immune homeostasis in healthy individuals. In cancer and, in particular, in hematological malignancies, Tregs exert a major immunosuppressive activity, thus playing a critical role in tumor cell growth, proliferation, and survival. Here, we summarize published data on the prognostic significance of Tregs in hematological malignancies and show that they are highly conflicting. The heterogeneity of the experimental approaches that were used explains—at least in part—the discordant results reported by different groups that have investigated the role of Tregs in cancer. In fact, different tissues have been studied (i.e., peripheral blood, bone marrow, and lymph node), applying different methods (i.e., flow cytometry versus immunohistochemistry, whole blood versus isolated peripheral blood mononuclear cells versus depletion of CD25+ cells, various panels of monoclonal antibodies, techniques of fixation and permeabilization, and gating strategies). This is of relevance in order to stress the need to apply standardized approaches in the study of Tregs in hematological malignancies and in cancer in general.
Highlights
Regulatory T cells (Tregs) constitute a small-size subpopulation of CD4+ T cells, accounting for 1–4% of circulating CD4+ lymphocyte in humans, specialized in suppressive functions that control unwanted immune responses toward self-antigens and toward foreign antigens in the context of the immune tolerance [1].Gershon and Kondo from Yale University first proposed the existence of CD8+ T cells with suppressive activity more than 40 years ago [2]
The intracytoplasmic Forkhead helix box P3 (FoxP3), a transcription factor required for the development, maintenance, and function of Tregs was subsequently identified [6, 7]
We reviewed a large body of published papers conducting a PubMed literature search
Summary
Regulatory T cells (Tregs) constitute a small-size subpopulation of CD4+ T cells, accounting for 1–4% of circulating CD4+ lymphocyte in humans, specialized in suppressive functions that control unwanted immune responses toward self-antigens and toward foreign antigens in the context of the immune tolerance [1]. In 1995, Sakaguchi and coworkers identified Tregs in mouse as CD4+ T cells expressing surface interleukin-2 (IL-2) receptor α-chain (CD25) [3]. Baecher-Allan and coworkers, using flow cytometry and analyzing sorted cells in vitro, identified a very small subset of T cells with high expression of CD25 and regulatory function in humans [4]. The central role of this transcription factor is confirmed by the fact that a FoxP3 single gene mutation on the X chromosome induces in Scurfy mice a severe autoimmune/inflammatory disease. The absence of the heterodimeric IL-7 receptor (CD127) combined with CD4, CD25, and FoxP3, has been shown to better identify Tregs, avoiding the contamination from other cell populations such as activated effector T cells [9, 10]
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