title: Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8⁺ T cell function in vitro.
abstract: HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL-10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression.
authors: Rush University Medical Center, Departments of Immunology/Microbiology and Internal Medicine, Chicago, Illinois 60612, USA. basile_siewe@rush.edu.
authors: Basile
authors: B
authors: Siewe
authors: Jack T
authors: JT
authors: Stapleton
authors: Jeffrey
authors: J
authors: Martinson
authors: Ali
authors: A
authors: Keshavarzian
authors: Nazia
authors: N
authors: Kazmi
authors: Patricia M
authors: PM
authors: Demarais
authors: Audrey L
authors: AL
authors: French
authors: Alan
authors: A
authors: Landay
mesh_terms: D000328:Adult; D000368:Aged; D060151:B-Lymphocytes, Regulatory / Q000502:physiology*; D060890:B7-H1 Antigen / Q000502:physiology; D015415:Biomarkers; D023201:CD40 Ligand / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018450:Disease Progression; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008875:Middle Aged; D051193:Toll-Like Receptors / Q000502:physiology; D019562:Viral Load
chemical_list: D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D051193:Toll-Like Receptors; D016753:Interleukin-10; D023201:CD40 Ligand