Leishmania (Viannia) parasites are etiological agents of
cutaneous leishmaniasis in the New World.
Infection is characterized by a mixed Th1/Th2 inflammatory response, which contributes to disease pathology. However, the role of regulatory T cells (Tregs) in Leishmania (Viannia) disease pathogenesis is unclear. Using the mouse model of chronic L. (V.) panamensis
infection, we examined the hypothesis that Treg functionality contributes to control of pathogenesis. Upon
infection, Tregs (CD4(+)Foxp3(+)) presented with a dysregulated phenotype, in that they produced IFN-γ, expressed Tbet, and had a reduced ability to suppress T cell proliferation in vitro. Targeted ablation of Tregs resulted in enlarged lesions, increased parasite load, and enhanced production of
IL-17 and IFN-γ, with no change in
IL-10 and
IL-13 levels. This indicated that an increased inflammatory response was commensurate with
disease exacerbation and that the remaining impaired Tregs were important in regulation of disease pathology. Conversely, adoptive transfer of Tregs from naive mice halted
disease progression, lowered parasite burden, and reduced
cytokine production (IL-10, IL-13, IL-17, IFN-γ). Because Tregs appeared to be important for controlling
infection, we hypothesized that their expansion could be used as an immunotherapeutic treatment approach. As a proof of principle, chronically infected mice were treated with rIL-2/anti-IL-2 Ab complex to expand Tregs. Treatment transitorily increased the numbers and percentage of Tregs (draining lymph node, spleen), which resulted in reduced
cytokine responses, ameliorated lesions, and reduced parasite load (10(5)-fold). Thus,
immunotherapy targeting Tregs could provide an alternate treatment strategy for
leishmaniasis caused by Leishmania (Viannia) parasites.