title: Immunomodulation of host-protective immune response by regulating Foxp3 expression and Treg function in Leishmania-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.
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Bidisha Paul
authors: BP
authors: Chowdhury
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Shibali
authors: S
authors: Das
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Saikat
authors: S
authors: Majumder
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Kuntal
authors: K
authors: Halder
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Sweta
authors: S
authors: Ghosh
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Satabdi
authors: S
authors: Biswas
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India.
authors: Syamdas
authors: S
authors: Bandyopadhyay
authors: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata-700054, India subrata@bic.boseinst.ernet.in.
authors: Subrata
authors: S
authors: Majumdar
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D060908:CTLA-4 Antigen / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000032:analysis; D007155:Immunologic Factors / Q000008:administration & dosage*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C556062:IL10 protein, mouse; C508018:Il2ra protein, mouse; D007155:Immunologic Factors; D050856:Interferon Regulatory Factor-1; D053645:Interleukin-2 Receptor alpha Subunit; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; C106544:Tnfrsf18 protein, mouse; D016212:Transforming Growth Factor beta; C050016:lipoarabinomannan; D016753:Interleukin-10
keywords: Ara-LAM; Foxp3; IRF1; Leishmania donovani; TGF-β; regulatory T cell