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: Basile Siewe, Jack T Stapleton, Jeffrey Martinson, Ali Keshavarzian, Nazia Kazmi, Patricia M Demarais, Audrey L French, Alan Landay
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 93 Issue 5 Pg. 811-8 (May 2013) ISSN: 1938-3673 [Electronic] England
• PMID: 23434518 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• B7-H1 Antigen
• Biomarkers
• CD274 protein, human
• Toll-Like Receptors
• Interleukin-10
• CD40 Ligand

Topics

• Adult
• Aged
• B-Lymphocytes, Regulatory (physiology)
• B7-H1 Antigen (physiology)
• Biomarkers
• CD40 Ligand (physiology)
• CD8-Positive T-Lymphocytes (immunology)
• Disease Progression
• HIV (immunology)
• HIV Infections (immunology)
• Humans
• Immunophenotyping
• Interleukin-10 (biosynthesis)
• Lymphocyte Activation
• Middle Aged
• Toll-Like Receptors (physiology)
• Viral Load