Induction of IL-10 and TGFβ from CD4+CD25+FoxP3+ T Cells Correlates with Parasite Load in Indian Kala-azar Patients Infected with Leishmania donovani

Citation: Bhattacharya P, Ghosh S, Ejazi SA, Rahaman M, Pandey K, Ravi Das VN, et al. (2016) Induction of IL-10 and TGFβ from CD4+CD25+FoxP3+ T Cells Correlates with Parasite Load in Indian Kala-azar Patients Infected with Leishmania donovani. PLoS Negl Trop Dis 10(2): e0004422. doi:10.1371/journal.pntd.0004422
Published: February 1, 2016

Abstract
Leishmania_donovaniBackground: Visceral leishmaniasis (VL) is distinguished by a complex interplay of immune response and parasite multiplication inside host cells. However, the direct association between different immunological correlates and parasite numbers remains largely unknown.
Methodology/Principal Findings: We examined the plasma levels of different disease promoting/protective as well as Th17 cytokines and found IL-10, TGFβ and IL-17 to be significantly correlated with parasite load in VL patients (r = 0.52, 0.53 and 0.51 for IL-10, TGFβ and IL-17, respectively). We then extended our investigation to a more antigen-specific response and found leishmanial antigen stimulated levels of both IL-10 and TGFβ to be significantly associated with parasite load (r = 0.71 and 0.72 for IL-10 and TGFβ respectively). In addition to cytokines we also looked for different cellular subtypes that could contribute to cytokine secretion and parasite persistence. Our observations manifested an association between different Treg cell markers and disease progression as absolute numbers of CD4+CD25+ (r = 0.55), CD4+CD25hi (r = 0.61) as well as percentages of CD4+CD25+FoxP3+ T cells (r = 0.68) all correlated with parasite load. Encouraged by these results, we investigated a link between these immunological components and interestingly found both CD4+CD25+ and CD4+CD25+FoxP3+ Treg cells to secrete significantly (p<0.05) higher amounts of not only IL-10 but also TGFβ in comparison to corresponding CD25- T cells.
Conclusions/Significance: Our findings shed some light on source(s) of TGFβ and suggest an association between these disease promoting cytokines and Treg cells with parasite load during active disease. Moreover, the direct evidence of CD4+CD25+FoxP3+ Treg cells as a source of IL-10 and TGFβ during active VL could open new avenues for immunotherapy towards cure of this potentially fatal disease.

Author Summary: Visceral leishmaniasis (VL) is one of the most widespread parasitic diseases worldwide and is caused by kinetoplastid protozoa of the Leishmania donovani complex. The disease begins with internalization of L. donovani parasites and their multiplication within host macrophages followed subsequently by immune suppression. However, the immunological factors responsible for disease progression and their association with parasite dynamics are not completely understood. Herein, we investigated the correlation of different immune components (cytokines and cellular subsets) with parasite load and their involvement in the course of VL. Our study revealed a significant positive correlation between parasite load and plasma as well as antigen specific levels of IL-10 and TGFβ. In addition to cytokines, cellular subsets could also contribute to disease pathogenesis through their regulatory mechanisms. Our results indicate different Treg cell markers (absolute numbers of CD4+CD25+ and CD4+CD25hi and percentages of CD4+CD25+FoxP3+) to be strongly correlated with parasite load. Exploring an association between these immunological correlates revealed Treg cells to be the source of these cytokines during VL. Therefore, this study points to a significant role of IL-10, TGFβ and Treg cells in parasite load and active VL, providing evidence which could be helpful in devising new immunotherapeutic strategies against this disease.

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