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

Abstract

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 (CD24 hi CD27 + 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 CD24 hi CD38 hi 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.

Immunosuppressive Mechanisms of Regulatory B Cells

“…In accordance with mouse data, studies in healthy donors and HIV patients found an enrichment of IL-10-producing cells within TIM-1 + B cells. In patients with HIV infection, TIM-1 + B cells specific for HIV antigens suppressed IL-17 and IFN-γ production by HIV-specific CD8 + and CD4 + T cells, which was partially reversed by IL-10 blockade ( 293 , 511 ). Human IL-10 + TIM-1 + Bregs can also be found infiltrating tumors and have been described to suppress CD8 + and CD4 + T cell anti-tumor responses ( 323 , 512 , 513 ).…”

Regulatory Role of B Cells and Its Subsets in Hepatitis E Virus Infection

“…Similarly, elevated levels of IL-10 producing B cells were observed in patients with HIV, HCV and lymphocytic choriomeningitis virus (LCMV) infections and the increased IL-10 levels were correlated with suppression of T cells [ 35 ]. Different methods of stimulation could impact the induction of IL-10 production by Bregs [ 9 ]. Upon stimulation with CpG-B, an agonist of TLR-9, we observed an induction of TGF- β expression on B cells and these TGF- β + B cells were enriched in acute hepatitis E patients compared to recovered individuals and healthy controls.…”

“…We had further elucidated TGF-β1 as the regulatory molecule responsible for enhancement of Tregs in self-limiting HEV infection and use of TGF-β1 was suggested as a possible supplement for boosting Treg response towards recovery from severe hepatitis E [16]. IL-10 producing B cells are known to play a major role towards the induction and maintenance of Tregs [9]. Our current results definitely suggest participation of Bregs in the maintenance of immune homeostasis and may allude possible existence of Bregs-Tregs interactions in HEV disease pathogenesis.…”

“…The population of Bregs is relatively small (~less than 10%) under physiological conditions, but show substantial expansion in both patients and murine models of chronic inflammatory diseases, autoimmune diseases, infection, transplantation and cancer [5][6][7][8]. Bregs studies in human immunodeficiency virus (HIV) [9] and hepatitis B virus (HBV) infections [4] have indicated that the regulatory activities of Bregs are majorly interleukin-10 (IL-10) cytokine mediated, however immune regulation by production of transforming growth factor-beta (TGF-β) [10] and interleukin-35 (IL-35) [11] cytokines have also been reported. Phenotypically, subsets of Bregs have been defined as CD19 + CD24 hi CD38 hi immature/transitional B cells, CD19 + CD24 int CD38 int as mature B cells and CD19 + CD24 int CD38as memory B cells [12][13][14].…”

Myeloid-derived suppressor cells and the pathogenesis of human immunodeficiency virus infection

“…Under normal physiological conditions, different immune cell populations that belong to the innate immune system (e.g. innate-suppressor cells of myeloid origin called myeloidderived suppressor cells (MDSCs)) and/or the adaptive immune system (adaptive-suppressor cells including regulatory T (Treg) cells and regulatory B (Breg) cells) work together in harmony to terminate inflammation and revert back to the homeostatic state [6,7,[17][18][19]. On the other hand, it is essential to keep in mind that although immunosuppressive cells could have a positive impact in the context of containing inflammation [20], especially if this is accomplished as soon as they become activated, failure to achieve such a goal could result in unwanted consequences, as seen in chronic inflammatory pathological conditions, such as observed in different types of cancer, certain autoimmune disorders and various infections [6,20].…”