Dendritic cell Biology, Innate Immunity, Interferon regulatory factors (IRF), Toll like receptors (TLRs), Transcription Regulation of DC differentiation, Applied Immunology.
Summary of Research:
Dendritic cells (DCs) are heterogeneous cell populations, comprised of various subsets that collectively provide early innate immunity leading to subsequent adaptive immune responses. Plasmacytoid DCs (pDCs), CD8α+ DCs, CD4+ DCs and CD8-CD4- DCs are four major DC subsets in mouse spleen and bone marrow cultures. Among DCs, pDCs and CD8α+ DCs produce very high levels of type I Interferon (IFN) and IL12 respectively that help to establish anti-viral anti-microbial states in the body. In a simplified system of DC classification, CD8α+ DC and equivalent population from various tissues is classified as cDC1 whereas CD4+ DC equivalent population is classified as cDC2 subtype.
Members of Interferon regulatory factors (IRFs) play a critical role in DC development and functions. IRF4 and IRF8 together govern the molecular program regulating DC subset development and functional diversity. Studies from knockout mouse model led to identification of critical role for Inhibitor of DNA binding 2 (Id2), Basic leucine zipper transcription factor 3 (Batf3) in development of CD8α+ DC. We reported that Irf8 is upstream of Batf3 and Id2 in the classical CD8α+ DC developmental program and demonstrated that Batf3 and Id2 had a synergistic effect on Irf8 directed developmental process (J. Immunol. 2013, 191:5993-6001).
Analyzing of the effect of Irf8 on TGF-β super family specific gene expression in DCs in lab led to identification of Acvrl1, a type I TGF-β superfamily receptor, as a gene strongly induced by Irf8 expression. We showed that among various DC subtypes, Acvrl1 is differentially expressed in CD8α+ DCs. ACVRL1 signaling augmented Irf8-directed classical CD8α+ DC development. IRF8R294C mutation in BXH2 mice abolishes the development of CD8α+ DCs without impairing pDC development and eliminates production of IL12p40, while retaining that of type I IFNs. IRF8R294C mutant failed to induce ACVRL1 transcription which co-related with defect in development of CD8α+ DCs in BXH2 mice. Irf8 expression is essential for plasmacytoid DC and CD8α+ DC development and ACVRL1 signaling plays a pivotal role whereby it suppresses plasmacytoid DC development while enhancing that of CD8α+ DCs, thus contributing to DC diversity development. The major pathways and the detailed biochemical mechanisms regulating the DC development and functions remains poorly understood.
Main focus of my lab would be to understand the role of IRFs in DC biology and examining role of DC subsets in various pathological conditions.
Ramya Venkataraman, Dr. Yadhu Sharma, Ajay Kumar, Anshul Kushwaha, Rajkumar Mane, Ajay Bansal, Monika
• Ramalingaswami Re-entry Fellowship 2020-2021 of the Department of Biotechnology (DBT), Govt. of India.
• Mid-career scientist Award from Indian immunology Society (IIS).
- Rawat BS, Venkataraman R, Budhwar R, Tailor P* (2022) Methionine- and Choline-Deficient Diet Identifies an Essential Role for DNA Methylation in Plasmacytoid Dendritic Cell Biology J Immunology 208:881-897. *denotes corresponding author
- Chauhan KS, Das A, Jaiswal H, Saha I, Kaushik M, Patel VK, Tailor P* (2021) IRF8 and BATF3 interaction enhances the cDC1 specific Pfkfb3 gene expression. Cellular Immunology 371:104468. *denotes corresponding author
- Das A, Chauhan KS, Kumar H, Tailor P* (2021) Mutation in Irf8 Gene (Irf8 R294C) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs Frontiers in Immunology 12:758190. *denotes corresponding author
- Verma P, Biswas S, Yadav N, Khatri A, Siddiqui H, Panda JJ, Rawat BS, Tailor P, Chauhan VS. (2021) Delivery of a Cancer-Testis Antigen-Derived Peptide Using Conformationally Restricted Dipeptide-Based Self-Assembled Nanotubes Molecular Pharmacology 18:3832-3842.
- Dwivedy A, Mariadasse R, Ahmad M, Chakraborty S, Kar D, Tiwari S, Mani S, Tailor P, Majumdar T, Jeyakanthan J and Biswal BK. (2021) Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2. PLOS Computational Biology 17:e1009384.
- Tripathi A, Singh Rawat B, Addya S, Surjit M, Tailor P, Vrati S, Banerjee A (2021) Lack of Interferon Regulatory Factor 8 Associated with Restricted IFN-gamma expression Augmented Japanese Encephalitis Virus Replication in the Mouse Brain. J Virology 95:e00406-21.
- Mishra R, Bhattacharya S, Tailor P, Takaoka A, Kumar H (2020) MicroRNA-30e-5p has an Integrated Role in the Regulation of the Innate Immune Response during Virus Infection and Systemic Lupus Erythematosus. iScience 23:101322.
- Saha I, Jaiswal H, Mishra R, Nel HJ, Schreuder J, Kaushik M, Singh Chauhan K, Singh Rawat B, Thomas R, Naik S, Kumar H, Tailor P* (2020) RelB suppresses type I Interferon signaling in dendritic cells. Cellular Immunology 349:104043. *denotes corresponding author
- Kumari P, Saha I, Narayanan A, Narayanan S, Takaoka A, Senthil Kumar N, Tailor P and Kumar H (2017) Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways. Cell Death and Disease, 8:e3078.
- Verma R, Jaiswal H, Chauhan KS, Kaushik M and Tailor P* (2016) ACVRL1 signaling augments CD8α+ dendritic cell development. Cuttting Edge: J Immunology 197: 1129-1134. *denotes corresponding author
- Bradfute SB, Anthony SM, Stuthman KS, Ayithan N, Tailor P, Shaia CI, Bray M, Ozato K, Bavari S. (2015) Mechanisms of immunity in post-exposure vaccination against Ebola virus infection. PLoS One. 2015:e0118434.
- Jaiswal H, Kaushik M, Sougrat R, Gupta M, Dey A, Verma R, Ozato K and Tailor P* (2013) Batf3 and Id2 have a synergistic effect on Irf8-Directed classical CD8α+ dendritic cell development. J Immunol 191: 5993-6001. *denotes corresponding author
- Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C, Carotta S, Donovan CE, Goldman ML, Tailor P, Ozato K, Levy DE, Nutt SL, Calame K, Leonard WJ. (2009) Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31:941-52.
- Wang H, Lee C, Qi C, Tailor P, Feng J, Abbasi S, Atsumi T, Morse H III. (2008) IRF8 regulates B cell lineage specification, commitment and differentiation. Blood 112:4028-4038.
- Tailor P, Tamura T, Morse H III, Ozato K. (2008) The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood 111:1942-1845.
- Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss I, Kitani A and Strober W (2008) Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest. 118:545-559.
- Tailor P, Tamura T, Kong H, Kubota T, Kubota M, Borghi P, Gabrilele L, and Ozato K. (2007) Type I interferon induction in dendritic cells requires IRF-8 that effects the feedback phase of transcription. Immunity 27:228-239.
- Tailor P, Tamura T, Ozato K. (2006) IRF family proteins and type I interferon induction in dendritic cells. Cell Research 16:134-140.
- Tamura T, Tailor P, Yamaoka K, Kong H, Tsujimura H, O’shea J, Singh H, Ozato, K. (2005) IFN regulatory factor- 4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol. 174:2573-81.