Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+ T cell function in vitro

Journal of Leukocyte Biology

Jeffrey Martinson²  Patricia M. Demarais³  Alan Landay¹  Jack T. Stapleton⁴  Ali Keshavarzian²  Basile Siewe²  Nazia Kazmi²  Audrey L. French, and³ 

[1] Rush University Medical Center, Departments of Immunology/Microbiology and Internal Medicine, Chicago, Illinois, USA; Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands;Rush University Medical Center, Departments of Immunology/Microbiology and Internal Medicine, Chicago, Illinois, USA;;Rush University Medical Center, Departments of Immunology/Microbiology and Internal Medicine, Chicago, Illinois, USA; CORE Center/Stroger Hospital of Cook County, Chicago, Illinois, USA Iowa City Veterans Affairs Medical Center and the University of Iowa, Departments of Internal Medicine, Microbiology and Immunology, Iowa City, Iowa, USA;

关键词: immune activation;    immune exhaustion;    IL-10;   

DOI  :  10.1189/jlb.0912436

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown