Regulatory T Cells Suppress T Cell Activation at the Pathologic Site of Human Visceral Leishmaniasis

Ambak K Rai,Chandreshwar P Thakur,Dipendra K Mitra,Tulika Seth,Pushpendra Singh,Sandeep K Srivastava,Amar Singh,Francesco Dieli

doi:10.1371/journal.pone.0031551

Ambak K Rai, Chandreshwar P Thakur + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0031551

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Journal: PLoS ONE	Publication Date: Feb 8, 2012
Citations: 94	License type: CC BY 4.0

Affiliation: All India Institute of Medical Sciences

Abstract

Suppression of T cell response is thought to be involved in the pathogenesis of visceral leishmaniasis (VL). Regulatory T cell (Treg) mediated immune-suppression is reported in animal models of Leishmania infection. However, their precise role among human patients still requires pathologic validation. The present study is aimed at understanding the frequency dynamics and function of Treg cells in the blood and bone marrow (BM) of VL patients. The study included 42 parasitologically confirmed patients, 17 healthy contact and 9 normal bone marrow specimens (NBM). We show i) the selective accumulation of Treg cells at one of the disease inflicted site(s), the BM, ii) their in vitro expansion in response to LD antigen and iii) persistence after successful chemotherapy. Results indicate that the Treg cells isolated from BM produces IL-10 and may inhibit T cell activation in IL-10 dependent manner. Moreover, we observed significantly higher levels of IL-10 among drug unresponsive patients, suggesting their critical role in suppression of immunity among VL patients. Our results suggest that IL-10 plays an important role in suppression of host immunity in human VL and possibly determines the efficacy of chemotherapy.

Highlights

Th1 effector response supposedly contains Leishmania donovani (LD) infection while polarized Th2 like response compromises the immune containment of LD infection, at the pathologic site(s) of VL including bone marrow (BM) [1,2]
We demonstrate that the CD4+FoxP3+ Treg cells isolated from the disease site (BM) of VL patients are a source of IL-10 along with CD4+FoxP32 cells
Our results suggest that the Treg cell of VL patients, from the BM, responded to LD antigen with production of immuno-suppressive cytokine IL-10 (Fig. 4B)

Summary

Introduction

Th1 effector response supposedly contains Leishmania donovani (LD) infection while polarized Th2 like response compromises the immune containment of LD infection, at the pathologic site(s) of VL including bone marrow (BM) [1,2]. A critical unresolved issue is the state of immune suppression [6,7,8], in spite of the presence of Th1 effector immune response (IFN-c) [9] along with IL-4 [10] and IL-10 [11] at the disease site(s) among VL patients. Regulatory T cells (Treg) are viewed as a major suppressor of effector T cells (Teff) and their role in local immuno-suppression in mice model of CL is documented [3]. Some studies identified FoxP3- cells as the source of IL-10 in mice model of CL [13,14]. Similar report on the cellular source of IL-10 among VL patients is available [15]

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