HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-cells

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.

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

“…Importantly, our data demonstrate that when overexpressed, both Foxp3 isoforms are capable of converting conventional CD4 + CD25 -cells into Treg. These latter results confirm and extend the findings of three other studies in the human setting [13,15,16] and of several studies in mice [3,4,[17][18][19][20][21].…”

“…Currently, little is known about the cellular distribution and expression ratio of these human Foxp3 isoforms. Furthermore, conflicting reports appeared on the functional properties of human Foxp3 genes: while three studies reported conversion of conventional T cells into Treg after ectopic expression of Foxp3FL [13,15,16], another study failed to induce Treg after retroviral transduction of conventional T cells with either Foxp3FL or Foxp3DE2 [14].…”

Systemic and Local Characterization of Regulatory T Cells in a Chronic Fungal Infection in Humans

“…However, CCR4 is also crucial for homing of Th cells and Th2, mainly memory T cells, into inflamed skin (39). In fact, we found CD4 ϩ CD25 Ϫ T cells in the blood and lesions coexpressing CCR4 and CD45RO, a phenotype related to memory T cells (40).…”

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

“…Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig.…”