Myeloid dendritic cells isolated from tissues of SIV-infected Rhesus macaques promote the induction of regulatory T cells

Abstract

Objective To determine whether the ability of primary myeloid dendritic cells (mDC) to induce regulatory T cells (Treg) is affected by chronic SIV infection. Design Modulation of DC activity with the aim of influencing Treg frequency may lead to new treatment options for HIV and strategies for vaccine development. Methods Eleven chronically-infected SIV+ Rhesus macaques were compared with four uninfected animals. Immature and mature mDC were isolated from mesenteric lymph nodes and spleen by cell sorting and cultured with purified autologous nonTreg (CD4+CD25- T cells). CD25 and FOXP3 upregulation was used to assess Treg induction. Results The frequency of splenic mDC and plasmacytoid DC was lower in infected animals than in uninfected animals; their frequency in the mesenteric lymph nodes was not significantly altered, but the percentage of mature mDC was increased in the mesenteric lymph nodes of infected animals. Mature splenic or mesenteric mDC from infected animals were significantly more efficient at inducing Treg than mDC from uninfected animals. Mature mDC from infected macaques induced more conversion than immature mDC. Splenic mDC were as efficient as mesenteric mDC in this context and CD103 expression by mDC did not appear to influence the level of conversion. Conclusions Tissue mDC from SIV-infected animals exhibit an enhanced capability to induce Treg and may contribute to the accumulation of Treg in lymphoid tissues during progressive infection. The activation status of DC impacts this process but the capacity to induce Treg was not restricted to mucosal DC in infected animals.

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

“…Ϫ CD25 Ϫ CD4 ϩ T cells than mDCs of uninfected macaques (72). However, the contribution of mDC-mediated Treg conversion to the increased frequency of Tregs may depend on the stage of infection and/or the body compartment, as we recently found that blood mDCs infected in vitro with HIV were not able to convert non-Tregs into Tregs (P. Presicce, submitted for publication).…”

“…TGF-␤ levels are high during HIV infection (4, 30) and could thus promote increased conversion. Interestingly, although CD103 mDC ϩ has been reported to be critical for Treg conversion in gut-associated lymphoid tissue (GALT) (22, 88), our recent data showed that the increased capacity of mDCs from SIV-infected macaques to induce FOXP3 was not directly associated with the presence of CD103 ϩ DCs, suggesting that other molecules may be involved in this conversion (72). Potential candidates are PD-L1, whose expression is increased on mDCs during HIV/SIV infection (13), and IDO, also increased in HIV-exposed mDCs (78).…”

Dendritic cells primed with a chimeric plasmid containing HIV‐1‐ gag associated with lysosomal‐associated protein‐1 (LAMP/ gag ) is a potential therapeutic vaccine against HIV

“…Accordingly, DCs derived from patients with HIV present an impaired function and may not be fully effective in inducing specific T-cell responses (8,48). Some investigators have also proposed that in vivo HIV-1-infected DCs present an immature phenotype and may promote T-cell tolerance to HIV-1 (49,50). Therefore, stimulation of autologous DCs in vitro may overcome tolerance and promote HIV-specific stimulation.…”

HIV Nef Expression Favors the Relative Preservation of CD4+ T Regulatory Cells That Retain Some Important Suppressive Functions

“…Myeloid DC from SIV-infected animals show an enhanced potential to induce Treg in vitro (43). Higher proportion of Treg has also been postulated to be a by-product of immune activation (8,11,38), but this remains controversial (14).…”