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

Abstract

BackgroundVisceral 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 FindingsWe 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/SignificanceOur 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.

Causes and consequences of higher Leishmania infantum burden in patients with kala‐azar: a study of 625 patients

“…As described previously, immunosuppressive factors that affect acquired cellular immunity, such as age, gender, HIV infection status and nutrition status, seem to be associated with higher levels of parasitemia, which appear to be driven by the production of IL-10 and TGF-b, thereby inhibiting the production of c-interferon by T-cells [63,64]. Recently, Battacharya et al [23] showed that CD4+CD25+FoxP3+ T-regulatory cells were strongly associated with the parasite burden. After this immunosuppression, innate progressive systemic inflammation following an increasing parasite burden inside macrophages may initiate the release of inflammatory cytokines.…”

“…Recently, Battacharya et al . showed that CD4+CD25+FoxP3+ T‐regulatory cells were strongly associated with the parasite burden. After this immunosuppression, innate progressive systemic inflammation following an increasing parasite burden inside macrophages may initiate the release of inflammatory cytokines.…”

“…The parasite burden may also be used during follow-up of immunosuppressed patients as a marker of treatment success [13,[18][19][20][21][22]. A recent study in India reported an association between the parasite burden (as measured by qPCR of blood samples) and a patient's clinical profile, cytokine profile and final outcome [23]. While correlations between the parasite burden and clinical severity and death were not identified due to the small cohort of patients, the study found the parasite burden to be associated with disease duration, spleen size, and the IL-10 and T-regulatory cell profiles, determined by the CD4+ CD25+ FoxP3+ subset of T-cells.…”

T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load

“…The visceral organs are well-known homing organs of parasites [3]. Few studies from this viewpoint have been carried out using peripheral blood [21]. Suppression of the T cell response in VL is well demonstrated, and contributes to the dissemination of parasites in various visceral organs of reticulo-endothelial organs.…”

“…To address some of these issues, we focused our attention on the T effector and T reg cells in the BM of VL patients with HPL as opposed to LPL patients. Few studies from this viewpoint have been carried out using peripheral blood [21]. However, a correlation between immune parameters with parasitic load at the BM remains to be resolved.…”