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Regulatory T Cells Diminish HIV Infection in Dendritic Cells - Conventional CD4(+) T Cell Clusters.

ABSTRACT: Formation of immunological synapses (IS) between dendritic cells (DCs) and conventional CD4(+) T cells (Tcon) is critical for productive immune responses. However, when DCs are HIV-infected such synapses are critical to establish HIV infection. As regulatory T cells (Treg) control DC-Tcon interactions, we inquired whether Treg might interfere with DC to Tcon HIV infection. We developed a model, using monocyte-derived DC infected with R5-HIV, and cultured with Tcon in the presence or absence of autologous Treg, using the physiological ratio of 1 Treg for 10 Tcon. Cultures containing Treg significantly decreased HIV infection in DC:T cell clusters. Notably, Treg appear to have an effect on the quality of the IS, as Treg decreased actin polymerization and DC maturation. Importantly, Treg decreased the trafficking of HIV punctate to the IS. Further, CD152 and cyclic adenosine monophosphate were critical Treg effector molecules, as their individual or simultaneous blockade abolished Treg activity, however no additive effect was found. Together, these data suggest that Treg can reduce HIV dissemination, which may be beneficial to the host in the early stages of infection.

SUBMITTER: Moreno-Fernandez ME

PROVIDER: S-EPMC4021135 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Regulatory T Cells Diminish HIV Infection in Dendritic Cells - Conventional CD4(+) T Cell Clusters.

Moreno-Fernandez Maria E ME Joedicke Jara J JJ Chougnet Claire A CA

Frontiers in immunology 20140508

Formation of immunological synapses (IS) between dendritic cells (DCs) and conventional CD4(+) T cells (Tcon) is critical for productive immune responses. However, when DCs are HIV-infected such synapses are critical to establish HIV infection. As regulatory T cells (Treg) control DC-Tcon interactions, we inquired whether Treg might interfere with DC to Tcon HIV infection. We developed a model, using monocyte-derived DC infected with R5-HIV, and cultured with Tcon in the presence or absence of a ...[more]

PMID: 24847325

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Project description:HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/μL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/μL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/μL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.

Project description:HIV infection provokes a myriad of pathological effects on the immune system where many markers of CD4+ T cell dysfunction have been identified. However, most studies to date have focused on single/double measurements of immune dysfunction, while the identification of pathological CD4+ T cell clusters that is highly associated to a specific biomarker for HIV disease remain less studied. Here, multi-parametric flow cytometry was used to investigate immune activation, exhaustion, and senescence of diverse maturation phenotypes of CD4+ T cells. The traditional method of manual data analysis was compared to a multidimensional clustering tool, FLOw Clustering with K (FLOCK) in two cohorts of 47 untreated HIV-infected individuals and 21 age and sex matched healthy controls. In order to reduce the subjectivity of FLOCK, we developed an "artificial reference", using 2% of all CD4+ gated T cells from each of the HIV-infected individuals. Principle component analyses demonstrated that using an artificial reference lead to a better separation of the HIV-infected individuals from the healthy controls as compared to using a single HIV-infected subject as a reference or analyzing data manually. Multiple correlation analyses between laboratory parameters and pathological CD4+ clusters revealed that the CD4/CD8 ratio was the preeminent surrogate marker of CD4+ T cells dysfunction using all three methods. Increased frequencies of an early-differentiated CD4+ T cell cluster with high CD38, HLA-DR and PD-1 expression were best correlated (Rho = -0.80, P value = 1.96×10-11) with HIV disease progression as measured by the CD4/CD8 ratio. The novel approach described here can be used to identify cell clusters that distinguish healthy from HIV infected subjects and is biologically relevant for HIV disease progression. These results further emphasize that a simple measurement of the CD4/CD8 ratio is a useful biomarker for assessment of combined CD4+ T cell dysfunction in chronic HIV disease.

Dataset Information

Regulatory T Cells Diminish HIV Infection in Dendritic Cells - Conventional CD4(+) T Cell Clusters.

Publications

Regulatory T Cells Diminish HIV Infection in Dendritic Cells - Conventional CD4(+) T Cell Clusters.

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