Interleukin-10 Producing Regulatory B Cells Transformed CD4+CD25- Into Tregs and Enhanced Regulatory T Cells Function in Human Leprosy.

Mohd. Tarique,Huma Naz,Raza Ali Naqvi,Donthamshetty N. Rao,Chaman Saini,Alpana Sharma,Reeta Rai,Neena Khanna,Santosh V. Kurra,Mohd Suhail

doi:10.3389/fimmu.2018.01636

Abstract

Regulatory B cells (Bregs) are known to exhibit their regulatory functions through interleukin-10 (IL-10) cytokine which suppress inflammation. There are only a few studies explaining the phenotype and functioning of these cells in contribution to host immunity in leprosy. Here, we evaluated the role of IL-10 producing Bregs in the pathogenesis of leprosy and assessed their immunoregulatory effects on Tregs and effector T cells. We found an increased frequency of Bregs and increased expression of their immune modulatory molecules (IL-10, FoxP3, and PDL-1) in leprosy patients. The potential immunoregulatory mechanism of Bregs was also investigated using MACS sorted Teff (CD4+CD25−) and Treg (CD4+CD25+) cells were cocultured with Bregs to elucidate the effects of Bregs on effector T and regulatory T cells. Cell coculture results showed that purified Bregs cells from leprosy patients convert CD4+CD25− cells into CD4+CD25+ cells. Cell coculture experiments also demonstrated that leprosy derived IL-10 producing Bregs enhance FoxP3 and PD-1 expression in Tregs and enhanced Tregs activity. Blocking of IL-10 receptor confirmed that IL-10 producing Breg has immunomodulatory effect on Tregs and effector T cells as effector T cells are not converted into Tregs and enhanced expression of FoxP3 and PD-1 was not observed on Tregs. Collectively, these findings demonstrate that IL-10 producing Breg cells play an important mechanism in controlling the immunopathogenesis of leprosy and have an immunomodulatory effect on Tregs and effector T cells. Our findings may pave way for novel targets of IL-10 producing Bregs for immunotherapy in leprosy patients.

Highlights

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae, which primarily affects macrophages and Schwann cells from the peripheral nerves
We first analyzed the frequency of IL-10-producing B cells in the PBMCs of healthy controls and leprosy patients to determine whether Mycobacterium leprae infection induces Breg response in leprosy patients
PBMCs of all three groups stimulated with M. leprae sonicated antigen and intracellular IL-10 stained with CD3+ T cells and Tregs (CD4+CD25+FoxP3+) cells

Summary

Introduction

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae, which primarily affects macrophages and Schwann cells from the peripheral nerves. Role of B Regulatory Cells in Leprosy characterized by the Th1 immune response, high cell-mediated immunity, relative resistance to the pathogen, and localized infection. Lepromatous (multibacillary, BL/LL) pole the infection is associated with Th2 immune response, defective cell-mediated immune response, foamy macrophages in the dermis due to a very high number of bacilli, lesion on all over the body parts [2, 3]. Three immunologically unstable form lies in-between these forms, borderline tuberculoid (BT), borderline-borderline, and borderline lepromatous leprosy, presenting wavering characteristics between the two poles of the disease. Our laboratory had observed Th3 type immune response with the progression of leprosy (tuberculoid to lepromatous leprosy) [4]. We reported that another immunosuppressive population γδ T cells increased in the leprosy patients [7] and defective T cell immune response in leprosy [8, 9]

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