Marginal Zone B-Cell Populations and Their Regulatory Potential in the Context of HIV and Other Chronic Inflammatory Conditions

Abstract

Inflammation in the context of Human Immunodeficiency Virus (HIV) establishes early and persists beyond antiretroviral therapy (ART). As such, we have shown excess B-cell activating factor (BAFF) in the blood of HIV-infected progressors, as soon as in the acute phase, and despite successful ART. Excess BAFF was associated with deregulation of the B-cell compartment; notably, with increased frequencies of a population sharing features of both transitional immature (TI) and marginal zone (MZ) B-cells, we termed Marginal Zone precursor-like (MZp). We have reported similar observations with HIV-transgenic mice, Simian Immunodeficiency Virus (SIV)-infected macaques, and more recently, with HIV-infected Beninese commercial sex workers, which suggests that excess BAFF and increased frequencies of MZp B-cells are reliable markers of inflammation in the context of HIV. Importantly, we have recently shown that in healthy individuals, MZps present an important regulatory B-cell (Breg) profile and function. Herein, we wish to review our current knowledge on MZ B-cell populations, especially their Breg status, and that of other B-cell populations sharing similar features. BAFF and its analog A Proliferation-Inducing Ligand (APRIL) are important in shaping the MZ B-cell pool; moreover, the impact that excess BAFF-encountered in the context of HIV and several chronic inflammatory conditions-may exert on MZ B-cell populations, Breg and antibody producing capacities is a threat to the self-integrity of their antibody responses and immune surveillance functions. As such, deregulations of MZ B-cell populations contribute to autoimmune manifestations and the development of MZ lymphomas (MZLs) in the context of HIV and other inflammatory diseases. Therefore, further comprehending the mechanisms regulating MZ B-cell populations and their functions could be beneficial to innovative therapeutic avenues that could be deployed to restore MZ B-cell immune competence in the context of chronic inflammation involving excess BAFF.

Keywords: B-cell activating factor (BAFF); Bregs; HIV; marginal zone (MZ) B-cells.

Figure 1

Ontogeny of postnatal B-cells.

Figure 2

MZp immune functions and how they can be affected in the HIV context. MZps possess a strong Breg potential, as attested by the expression of several immunoregulatory molecules. Indeed, MZps express CD39 and CD73, which will convert the extracellular ATP into ADO. This molecule will then be uptaken by purinergic receptors such as A2_A, which will induce cAMP accumulation in the cytosol and the activation of the CREB pathway. CREB will induce the expression of CREB-induced elements such as the NR4A molecules and IL-10, which will allow for the maintenance of a regulatory phenotype. The NR4As will then induce the expression of even more immunoregulatory molecules such as CD83 and PD-L1, while also impeding unwanted cell activation by the BCR or the TLR. However, this homeostasis is heavily altered in the HIV context due to the chronic inflammation, excess BAFF and viral proteins. For instance, MZ B-cells are able to class-switch following CD40 engagement and subsequent NF-kB pathway activation. However, in the HIV context, HIV Nef could impede this CSR. HIV gp120 could activate B-cells by cross-linking DC-SIGN an action that is enhanced by BAFF. Excess BAFF could induce TACI-dependent CSR by activating the mTOR pathway, which intersects with the TLR pathway (also engaged due to HIV-mediated recognition by TLR7, expressed by MZ B-cells), lowering the MZ activation threshold. HIV proteins such as Vpr could also directly affect MZp immunoregulatory protein expression such as CD83. Thus, in the HIV context, MZps could possibly lose their immunoregulatory functions, become easily activated and produce poor-affinity antibodies, with possible auto-reactivity.