Expansion of Parasite-Specific CD4+ and CD8+ T Cells Expressing IL-10 Superfamily Cytokine Members and Their Regulation in Human Lymphatic Filariasis

Rajamanickam Anuradha,Luke E Hanna,Thomas B Nutman,Thomas B Nutman,Parakkal Jovvian George,Vedachalam Chandrasekaran,Subash Babu,Subash Babu,Subash Babu,Paul Kumaran,Sabine Specht

doi:10.1371/journal.pntd.0002762

Abstract

BackgroundLymphatic filariasis (LF) is known to be associated with an increased production of IL-10. The role of the other IL-10 family members in the pathogenesis of infection and/or disease is not known.Methodology/Principal FindingsWe examined the expression patterns of IL-10 family members – IL-19, IL-24 and IL-26 in LF. We demonstrate that both CD4+ and CD8+ T cells express IL-19, IL-24 and IL-26 and that the frequency of CD4+ T cells expressing IL-19 and IL-24 (as well as IL-10) is significantly increased at baseline and following filarial antigen stimulation in patients with LF in comparison to individuals with filarial lymphedema and uninfected individuals. This CD4+ T cell expression pattern was associated with increased production of IL-19 and IL-24 by filarial – antigen stimulated PBMC. Moreover, the frequency of CD4+ and CD8+ T cells expressing IL-26 was significantly increased following filarial antigen stimulation in filarial lymphedema individuals. Interestingly, IL-10 blockade resulted in diminished frequencies of IL-19+ and IL-24+ T cells, whereas the addition of recombinant IL-10 resulted in significantly increased frequency of IL-19+ and IL-24+ T cells as well as significantly up regulated IL-19 and IL-24 gene expression, suggesting that IL-10 regulates IL-19 and IL-24 expression in T cells. In addition, IL-1β and IL-23 blockade also induced a diminution in the frequency of IL-19+ and IL-24+ T cells, indicating a novel role for these cytokines in the induction of IL-19 and IL-24 expressing T cells. Finally, elimination of infection resulted in significantly decreased frequencies of antigen – specific CD4+ T cells expressing IL-10, IL-19 and IL-24.ConclusionsOur findings, therefore, suggest that IL-19 and IL-24 are associated with the regulation of immune responses in active filarial infection and potentially with protection against development of pathology, while IL-26 is predominantly associated with pathology in LF.

Highlights

Lymphatic filariasis (LF) is associated with a variety of clinical outcomes [1]
Our findings, suggest that IL-19 and IL-24 are associated with the regulation of immune responses in active filarial infection and potentially with protection against development of pathology, while IL-26 is predominantly associated with pathology in LF
To determine the association of IL-10 and the related family members IL-19, IL-24 and IL-26 in protection from pathology and in susceptibility to or resistance to clinically apparent disease in LF, we measured the frequency of CD4+ T cells expressing these cytokines in INF individuals and in those with LF-associated disease (CP) or UN individuals (Figure 1A)

Summary

Introduction

The most intriguing and common clinical manifestation of LF is the subclinical condition associated with circulating microfilariae or circulating adult worm antigen [2]. Asymptomatic LF has been shown to be associated with impaired parasite – specific proliferative responses as well as a down regulation of CD4+ T cell responses [3]. Unlike the clinically asymptomatic infection, filarial disease has been associated with increased frequencies of CD4+ T cells expressing IFNc in response to parasite antigen [6] and elevated production of pro-inflammatory Th1 and Th17 cytokines [7] possibly driven by microbial products translocated through lymphatic endothelium [8]. Lymphatic filariasis (LF) is known to be associated with an increased production of IL-10. The role of the other IL-10 family members in the pathogenesis of infection and/or disease is not known

Methods

Results

Discussion

Conclusion