Immunomodulation of host-protective immune response by regulating Foxp3 expression and Treg function inLeishmania-infected BALB/c mice: critical role of IRF1

Abstract

Visceral leishmaniasis (VL), caused by a protozoan parasite Leishmania donovani, is still a threat to mankind due to treatment failure, drug resistance and coinfection with HIV. The limitations of first-line drugs have led to the development of new strategies to combat this dreaded disease. Recently, we have shown the immunomodulatory property of Ara-LAM, a TLR2 ligand, against leishmanial pathogenesis. In this study, we have extended our study to the effect of Ara-LAM on regulatory T cells in a murine model of VL. We observed that Ara-LAM-treated infected BALB/c mice showed a strong host-protective Th1 immune response due to reduced IL-10 and TGF-β production, along with marked decrease in CD4(+) CD25(+) Foxp3(+) GITR(+) CTLA4(+) regulatory T cell (Treg) generation and activation. The reduction in Foxp3 expression was due to effective modulation of TGF-β-induced SMAD signaling in Treg cells by Ara-LAM. Moreover, we demonstrated that Ara-LAM-induced IRF1 expression in the Treg cells, which negatively regulated foxp3 gene transcription, resulting in the reduced immunosuppressive activity of Treg cells. Interestingly, irf1 gene knockdown completely abrogated the effect of Ara-LAM on Treg cells. Thus, these findings provide detailed mechanistic insight into Ara-LAM-mediated modulation of Treg cells, which might be helpful in combating VL.

Seminal Plasma Modifies the Transcriptional Pattern of the Endometrium and Advances Embryo Development in Pigs

“…To ensure that sufficient T reg cells are present in the implantation area, their activation and proliferation during the preimplantation period are crucial. In the present study, some T reg -associated genes were found to be upregulated in SPtreated endometrium, including DLG1, FAS, LGALS1, STAT5A, and IRF1 in the uterine horn distal region (52)(53)(54)(55)(56). None of these genes or others associated with T reg cells were altered in the proximal uterine region.…”

EBI-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity

“…During viral infection, targeting EBI-3 led to cure (14). The suppressive activities of IL-10 (46, 47) and TGF-β (48–50) and their contribution in murine VL are well established (51). Subsequently, Murray and colleagues proposed targeting IL-10 by neutralizing antibodies as a promising immunotherapy against murine VL (22, 46).…”

Leishmania species‐dependent functional duality of toll‐like receptor 2

“…The treatment with Ara‐LAM restricts L. donovani replication in target organs through mechanisms including improved CD8 + T‐cells recruitment and functions, enhanced Th1 responses, and suppressed T‐reg activity . Ara‐LAM also leads to the T‐bet induction, which activates effector CD8 + T‐cells that is reflected in the elevated expression of the IFN‐γ, granzyme‐B, perforin and in an NF‐κB and MAPK‐dependent process in VL (Figure ).…”

“…It also modulates the IRF4 and IRF8 expression and reduces parasite burden in liver and spleen of BALB/c mice infected with L. donovani . Thus, the Ara‐LAM‐mediated improved IFN‐γ responsiveness is a novel principle that can be utilized to generate immunity against L. donovani in a susceptible host …”