Research Article: Analysis of the dysregulation between regulatory B and T cells (Breg and Treg) in human immunodeficiency virus (HIV)-infected patients

Date Published: March 27, 2019

Publisher: Public Library of Science

Author(s): Carolina Gutiérrez, Jacobo Lopez-Abente, Verónica Pérez-Fernández, Adrián Prieto-Sánchez, Rafael Correa-Rocha, Santiago Moreno-Guillen, María-Ángeles Muñoz-Fernández, Marjorie Pion, Chang H. Kim.


This study examines the relationship between regulatory B (Breg) and T (Treg) compartments, which play crucial roles in the maintenance of immune homeostasis in the context of HIV. Using flow cytometry, the phenotypes of different Breg and Treg subsets from HIV-infected and healthy individuals were analyzed, along with the suppressive capacity of Breg. Peripheral blood samples of thirteen HIV+ treatment-naïve individuals, fourteen treated-HIV+ individuals with undetectable viral load and twelve healthy individuals were analyzed. The absolute counts of Breg and Treg subsets were decreased in HIV+ treatment-naïve individuals in comparison to treated-HIV+ and healthy individuals. Interestingly, correlations between Breg subsets (CD24hiCD27+ and PD-L1+ B cells) and IL-10-producing Breg observed in healthy individuals were lost in HIV+ treatment-naïve individuals. However, a correlation between frequencies of CD24hiCD38hi or TIM-1+-Breg subsets and Treg was observed in HIV+ treatment-naïve individuals and not in healthy individuals. Therefore, we hypothesized that various Breg subsets might have different functions during B and T-cell homeostasis during HIV-1 infection. In parallel, stimulated Breg from HIV-infected treatment-naïve individuals presented a decreased ability to suppress CD4+ T-cell proliferation in comparison to the stimulated Breg from treated-HIV+ or healthy individuals. We demonstrate a dysregulation between Breg and Treg subsets in HIV-infected individuals, which might participate in the hyper-activation and exhaustion of the immune system that occurs in such patients.

Partial Text

HIV infection induces a general dysregulation of the immune system (IS), which can be defined as unrestrained or unregulated immune responses. In the case of the HIV, this implies a general loss of immune cell function and chronic inflammation, which lead to immune exhaustion, where almost all cells of the IS lose their functional ability. B and T cell exhaustion is characterized by an increase of the activated phenotype, a decrease of proliferative ability, and the loss of their effector capacity. These outcomes are related to uncontrolled viral persistence and disease progression [1, 2]. Recently, regulatory B and T cells (Breg and Treg, respectively) have been described to participate in the maintenance of immune homeostasis, of which one aim is to suppress the over-reaction in the case of inflammation, which leads to an appropriate immune response [3–5].

To our knowledge, this is the first time that the relationships between regulatory immune cell compartments where a general dysregulation of phenotype and function occur have been defined. We observed no changes or slight increases in the frequency of the Breg subsets and decreases in the absolute counts in HIV+ treatment-naïve individuals in comparison to healthy individuals. No changes were observed in the frequency of IL-10-producing Breg subsets or total IL-10-producing B cells. Our results differ from previous works that described an increase in IL-10-producing total B cells [35] and IL-10-producing CD19+CD24hiCD38hi [16, 19, 35]. However, the major difference in our work is that we studied IL-10 intracellular expression in PBMCs stimulated with a mix of stimuli (CD40L, CpG and LPS) that induces a Breg phenotype. This contrasts with other works where the labeling was performed directly on freshly isolated PBMCs stimulated with PMA+ionomycin [18, 19, 35]. Another study on common variable immunodeficiency showed that Breg were defective in IL-10 expression and that the frequency of IL-10-producing CD24hiCD38hi or CD24hiCD27+ B cells was decreased when the cell culture contained CpG [36]. Therefore, the induction of IL-10 production by Breg is highly dependent on the type of stimulation used.




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