Abstract
A T-cell subset, defined as CD4+CD25hi (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4+ T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4+ and higher levels of activated T-cells have greatly reduced levels of FoxP3+CD4+CD25hi T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.
Highlights
Isolation and Characterization of Human Treg Cells To analyze susceptibility of Treg cells to HIV infection, we first developed a method to isolate these cells from peripheral blood
Previous studies suggested that human Treg cells resided within the CD45ROþCD25hi subset (Baecher-Allan et al 2001; Taams et al 2001)
Treg cells expressed high levels of CCR5 and CCR4 compared to memory and naıve T-cells, while expression of CXCR4 and CCR7 was lower and CXCR3 expression was similar as compared to memory T-cells (Figure 1B)
Summary
There is compelling evidence that a subset of T-cells with regulatory activity suppresses T-cell activation in both mice and humans (Sakaguchi et al 1995; Asano et al 1996; Suri-Payer et al 1998; Takahashi et al 1998; Thornton and Shevach 1998; Baecher-Allan et al 2001; Dieckmann et al 2001; Jonuleit et al 2001, 2002; Levings et al 2001; Ng et al 2001; Taams et al 2001). Regulatory T-cells (Treg cells) have been shown to inhibit various autoimmune and allergic diseases (Shevach 2000; Furtado et al 2001; Curotto de Lafaille and Lafaille 2002; Green et al 2002, 2003; McHugh and Shevach 2002), mediate transplantation and self-tolerance (Sakaguchi et al 1995; Hara et al 2001; Taylor et al 2001, 2002; Sanchez-Fueyo et al 2002), and block the activation and proliferation of T-cells both in vitro and in vivo (Takahashi et al 1998; Thornton and Shevach 1998; Annacker et al 2000, 2001). Treg cells have been shown to express high levels of certain chemokine receptors such as CCR4 and CCR8 (Iellem et al 2001)
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