Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function

By M. Levings, R. Sangregorio, M. Roncarolo. Journal of Experimental Medicine, 2001

1,136 citations recorded by the source corpus.

Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4+ Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25+CD4+ Tr cells in humans has not been reported. Here we show that human CD25+CD4+ Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor–mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte–associated antigen (CTLA)-4. Human CD25+CD4+ Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-β, low levels of interferon (IFN)-γ, and no IL-4 or IL-2. Importantly, CD25+CD4+ Tr cells strongly inhibited the proliferative responses of both naive and memory CD4+ T cells to alloantigens, but neither IL-10, TGF-β, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25+CD4+ Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25+CD4+ Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell–mediated diseases.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/80eb208944ab04e90e32310ecf07c1e4ed2a3132

How researchers see this paper

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In Immunology

1. Shimon Sakaguchi
2. K. Wing
3. P. Krammer
4. Angelika Schmidt
5. Nina Oberle
6. M. Miyara
7. Naganari Ohkura
8. Tomoyuki Yamaguchi

In Oncology

1. Craig B. Thompson
2. P. Krammer
3. M. Battaglia
4. Shimon Sakaguchi
5. C. June
6. E. Shevach

Citations in the corpus

• Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells1 (2004, background): “Such an intracellular and surface upregulation of CTLA-4 has been reported for human Treg after activation in vitro (28), supporting the idea that infiltrating CD4 CD25 T cells were activated at the tumor site.”
• Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. (2004, background): “…cells, CD4+CD25+ Treg cells play a role in the induction of tolerance (Sakaguchi et al., 1995; Taylor et al., 2001; Beacher-Allan et al., 2001; Jonuleit et al., 2001; Levings et al., 2001; Ng et al., 2001; Stephens et al., 2001; Cohen et al., 2002; Hoffmann et al., 2002; Word and Sakaguchi, 2003).”
• Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. (2005, background): “CD4CD25 cells are also distinguishable from CD4CD25 cells by their elevated expression of CTLA-4 (CD152, 38%) which has been reported previously for human circulating regulatory T cells (28) as well as HLA class II molecule (27%).”
• T-cell regulation by CD28 and CTLA-4 (2001, background): “However, blockade of CTLA-4 had no effect on regulatory function of these cell”