Major areas of research in the lab include:
Stem cells in normal hematopoiesis and leukemia
Stem cells manifest a unique capacity to differentiate into various cell types while maintaining their own number in an undifferentiated state. Thus, a single hematopoietic stem cell (HSC) can regenerate the entire blood system, enabling the life-saving bone marrow transplantation procedure. Paradoxically, the role and properties of HSC during normal blood production (hematopoiesis) in unirradiated organisms remain controversial. We have developed genetic systems that identify and trace HSC, and showed that these cells are indeed a major source of adult hematopoiesis. Current studies are focused on the mechanisms of HSC differentiation in normal conditions and their subversion in leukemia.
Dendritic cell development and function
Dendritic cells (DC) detect, capture and "present" invading pathogens to lymphocytes, thus representing a critical link between the innate and adaptive immunity. Dendritic cells include several lineages dedicated to distinct pathogens and immune response types, including the classical DCs (cDCs) and interferon-producing plasmacytoid DC (pDCs). Our studies have identified several transcription factors and signaling pathways that control the development and specification of DCs. Current studies focus on the molecular control of DC function in the steady state and during immune responses.
Mechanisms of autoimmunity
Aberrant recognition and attack of the body by its own immune system causes autoimmune diseases such as type I diabetes, multiple sclerosis and systemic lupus erythematosus (SLE). We are studying the mechanisms of autoimmune responses focusing on SLE, in which self-DNA and RNA are being targeted by the immune system. Recently, we have characterized a unique nuclease, DNASE1L3, as an essential mechanism of tolerance to self-DNA whose loss causes SLE-like autoimmunity focused on self-DNA. We are exploring the mechanism of DNASE1L3 activity and its potential as a therapeutic tool.
Stem cells in normal hematopoiesis and leukemia
Galan-Caridad JM, Harel S, Arenzana TL, Hou ZE, Doetsch FK, Mirny LA, Reizis B. Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell. 2007 Apr 20;129(2):345-57.
Weisberg SP, Smith-Raska MR, Esquilin JM, Zhang J, Arenzana TL, Lau CM, Chirchill M, Pan H, Klinakis A, Dixon JE, Mirny LA, Mukherjee S, Reizis B. ZFX controls the propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia. Cell Reports. 2014 Feb 13;6(3):528-40.
Sawai CM, Babovic S, Upadhaya S, Knapp DJHF, Lavin Y, Lau CM, Goloborodko A, Feng J, Fujisaki J, Ding L, Mirny LA, Merad M, Eaves CJ, Reizis B. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity. 2016 Sep 20;45(3):597-609.
Upadhaya S, Sawai CM, Papalexi E, Rashidfarrokhi A, Jang G, Chattopadhyay P, Satija R, Reizis B. Kinetics of adult hematopoietic stem cell differentiation in vivo. J Exp Med. 2018 Nov 5;215(11):2815-2832.
Upadhaya S, Krichevsky O, Akhmetzyanova I, Sawai CM, Fooksman DR, Reizis B. Intravital Imaging Reveals Motility of Adult Hematopoietic Stem Cells in the Bone Marrow Niche. Cell Stem Cell. 2020 Aug 6;27(2):336-345.e4.
Dendritic cells development and function
Caton ML, Smith-Raska MR, Reizis B. Notch–RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J Exp Med. 2007 Jul 9;204(7):1653-64.
Birnberg T; Bar-On L, Sapoznikov A, Caton ML, Cervantes-Barragán L, Makia D, Krauthgamer R, Brenner O, Ludewig B, Brockschnieder D, Riethmacher D, Reizis B*, Jung S*. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity. 2008 Dec;29(6):986-97. (* joint corresponding authorship)
Sathaliyawala T, O’Gorman WE, Greter M, Bogunovic M, Konjufca V, Hou ZE, Nolan GP, Miller MJ, Merad M, Reizis B. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity. 2010 Oct;33(4):597-606.
Lewis KL, Caton ML, Bogunovic M, Greter M, Grajkowska LT, Ng D, Klinakis A, Charo IF, Jung S, Gommerman JL, Ivanov II, Liu K, Merad M, Reizis B. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity. 2011 Nov 23;35(5):780-91.
Lau CM, Nish SA, Yogev N, Waisman A, Reiner SL, Reizis B. Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses. J Exp Med. 2016 Mar 7;213(3):415-31.
Kirkling ME, Cytlak U, Lau CM, Lewis KL, Resteu A, Khodadadi-Jamayran A, Siebel CW, Salmon H, Merad M, Tsirigos A, Collin M, Bigley V, Reizis B. Notch Signaling Facilitates In Vitro Generation of Cross-Presenting Classical Dendritic Cells. Cell Rep. 2018 Jun 19;23(12):3658-3672.e6.
Lau CM, Tiniakou I, Kirkling ME, Yap GS, Hock H, Reizis B. Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells. J Exp Med. 2018, e-pub ahead of print.
Feng J, Pucella JN, Jang G, Alcántara-Hernández M, Upadhaya S, Adams NM, Khodadadi-Jamayran A, Lau CM, Stoeckius M, Hao S, Smibert P, Tsirigos A, Idoyaga J, Reizis B. Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells. Immunity 2022 Mar 8;55(3):405-422
Plasmacytoid dendritic cells
Cisse B, Caton ML, Lehner M, Maeda T, Scheu S, Locksley R, Holmberg D, Zweier C, den Hollander NS, Kant SG, Holter W, Rauch A, Zhuang Y, Reizis B. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell. 2008 Oct. 3;135(1):37-48.
Ghosh HS, Cisse B, Bunin A, Lewis KL, Reizis B. Continuous expression of the transcription factor E2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity. 2010 Dec 14;33(6):905-16
Cervantes-Barragan L, Lewis KL, Firner S, Thiel V, Hugues S, Reith W, Ludewig B*, Reizis B*. Plasmacytoid dendritic cells control T-cell response to chronic viral infection. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3012-7. (* joint senior authorship)
Sawai CM, Sisirak V, Ghosh HS, Hou ZE, Ceribelli M, Staudt LM, Reizis B. Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells. J Exp Med. 2013 Oct 21;210(11):2151-9.
Ghosh HS, Ceribelli M, Matos I, Lazarovici A, Bussemaker H, Lasorella A, Hiebert SW, Liu K, Staudt LM, Reizis B. ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. J Exp Med. 2014 Jul 28;211(8):1623-35.
Bunin A, Sisirak V, Ghosh HS, Grajkowska LT, Hou ZE, Miron M, Yang C, Ceribelli M, Uetani N, Chaperot L, Plumas J, Hendriks W, Tremblay ML, Haecker H, Staudt LM, Green PH, Bhagat G, Reizis B. Protein tyrosine phosphatase PTPRS is a specific inhibitory receptor on plasmacytoid dendritic cells. Immunity. 2015 Aug 18;43(2):277-88.
Ceribelli M, Hou ZE, Kelly PN, Huang DW, Wright G, Ganapathi K, Evbuomwan MO, Pittaluga S, Shaffer AL, Marcucci G, Forman SJ, Xiao W, Guha R, Zhang X, Ferrer M, Chaperot L, Plumas J, Jaffe ES, Thomas CJ, Reizis B*, Staudt LM*. A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell. 2016 Nov 14;30(5):764-778. (*joint corresponding authors).
Grajkowska LT, Ceribelli M, Lau CM, Warren ME, Tiniakou I, Nakandakari Higa S, Bunin A, Haecker H, Mirny LA, Staudt LM, Reizis B. Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification. Immunity. 2016 Dec 8 [Epub ahead of print]
Sawai CM, Serpas L, Neto AG, Jang G, Rashidfarrokhi A, Kolbeck R, Sanjuan MA, Reizis B*, Sisirak V*. Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease. Front Immunol. 2018 Oct 25;9:2475. (*joint corresponding authors).
Yun TJ, Igarashi S, Zhao H, Perez OA, Pereira MR, Zorn E, Shen Y, Goodrum F, Rahman A, Sims PA, Farber DL, Reizis B. Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells. Sci Immunol. 2021 Apr 2;6(58):eabc7302.
Mechanisms of autoimmunity
Sisirak V, Ganguly D, Lewis KL, Couillault C, Tanaka L, Bolland S, D'Agati V, Elkon KB, Reizis B. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med. 2014 Sep 22;211(10):1969-76.
Sisirak V, Sally B, D’Agati V, Martinez-Ortiz W, Özçakar ZB, David J, Rashidfarrokhi A, Yeste A, Panea C, Bogunovic M, Ivanov II, Quintana FJ, Sanz I, Elkon KB, Tekin M, Yalçınkaya F, Cardozo TJ, Clancy RM, Buyon JP, Reizis B. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell. 2016 Jun 30;166(1):88-101.
Serpas L, Chan RWY, Jiang P, Ni M, Sun K, Rashidfarrokhi A, Soni C, Sisirak V, Lee WS, Cheng SH, Peng W, Chan KCA, Chiu RWK, Reizis B*, Lo YMD*. Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA. Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):641-649. (*joint corresponding authors).
Soni C, Perez OA, Voss WN, Pucella JN, Serpas L, Mehl J, Ching KL, Goike J, Georgiou G, Ippolito GC, Sisirak V, Reizis B. Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA. Immunity. 2020 Jun 16;52(6):1022-1038.e7.
Hartl J, Serpas L, Wang Y, Rashidfarrokhi A, Perez OA, Sally B, Sisirak V, Soni C, Khodadadi-Jamayran A, Tsirigos A, Caiello I, Bracaglia C, Volpi S, Ghiggeri GM, Chida AS, Sanz I, Kim MY, Belmont HM, Silverman GJ, Clancy RM, Izmirly PM, Buyon JP, Reizis B. Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus. J Exp Med. 2021 May 3;218(5):e20201138.
