Immunobiology

During hematopoiesis, hematopoietic stem cells (HSCs) give rise to all blood cells, including erythroid, myeloid and lymphoid lineages. The self-renewal and hematopoietic differentiation of HSCs are strictly controlled by both extrinsic and intrinsic signals. B cells, a subtype of lymphoid cells, are critical to the immune defense, and their development and function are also highly regulated by signals derived from a variety of cell surface receptors. Abnormal signals from the receptors often lead to hematological and immunological diseases, including hematopoietic malignancies, and immunodeficiency and autoimmune diseases. Our research focuses on identifying and functionally characterizing signaling molecules that are important for HSC and B cell biology. Our research employs multiple cutting-edge approaches, including the targeted gene disruption, transgenic, and bone marrow transplantation technologies.

Cytokine Receptor Signaling

Upon binding of cytokines, cytokine receptors initiate signals to regulate a variety of cellular responses, including cell growth, survival, differentiation, and function during hematopoiesis. Engagement of cytokine receptors induces the activation of the JAK family of cytoplasmic protein tyrosine kinases. In turn, JAKs activate components of diverse signal transduction pathways, including members of the Signal Transducers and Activators of Transcription (Stat). The importance of the JAKs and Stats in signaling has been emphasized by gene disruption studies. Dysregulation of JAK/Stat pathway has been implicated in the pathogenesis of numerous hematological diseases. One of our current research projects studies the regulation and function of Stat5 proteins.

In addition, Gimap5 (GTPase of the Immune-Associated Protein 5) is a member of a novel family of guanosine nucleotide-binding proteins. Our recent studies discover that Gimap5 plays a critical role in the survival of HSCs and hematopoietic progenitor cells. Gimap5 enhances interaction between Mcl-1 and HSC70, thus preventing Mcl-1 degradation and maintaining mitochondrial integrity. One of our current research projects studies the molecular mechanism by which Gimap5 regulates the survival of HSCs as well as the role of Gimap5 in regulating leukemia stem cells.

B Cell Receptor Signaling

B cells are one important component of the adaptive immune system. Signals from the B cell antigen receptor (BCR) and its surrogate predecessor pre-BCR are essential for the development, maintenance and function of B cells. Improper signals from pre-BCR/BCR often result in immunodeficiency, autoimmunity, and B-cell leukemia. During last decade, a wide variety of signaling molecules involved in BCR function have been discovered. Our current research projects aim to fully understand the pre-BCR/BCR signal transduction cascade by identifying novel signaling molecules of the pre-BCR/BCR. Our current research projects also study the molecular mechanism by which signaling molecules, such as phospholipase Cγ (PLCγ), Bcl10, MALT1 and TAK1, activate NF-κB during BCR signaling and investigate the roles of these signaling molecules in pre-BCR/BCR-mediated B cell development and function in vivo.

The long term goals of our research program aim to establish a thorough understanding of the normal signaling pathways of the cytokine and pre-BCR/BCR receptors, to obtain new clues regarding the molecular pathogenesis of numerous hematological and immunological diseases, including acute or chronic hematopoietic malignancies, and immunodeficiency (such as agammaglobulinemia and common variable immunodeficiency) and autoimmune (such as systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, multiple sclerosis, hemolytic anemia, and heparin-induced thrombocytopenia) diseases, and to aid in the development of novel therapeutic strategies for treatment of these hematological and immunological disorders.

• Zheng Y, Wang AW, Yu M, Padmanabhan A, Tourdot BE, Newman DK, White GC, Aster AH, Wen R, and Wang D.  B cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia.  Blood (in press).
• Yang XO, Zhang H, Kim BS, Niu X, Peng J, Chen Y, Kerketta R, Lee YH, Chang SH, Corry DB, Wang D, et al.  The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation.  Nat Immunol 14:732-740, 2013.
• Qi X, Hong J, Chaves L, Zhuang Y, Chen Y, Wang D, et al, and Huang H.  Antagonistic regulation by C/EBPalpha and MITF specifies basophil and mast cell fates.  Immunity 39:97-110; 2013.
• Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, Arepally G, and Wang D.  Critical role for mouse marginal zone B cells in PF4/heparin antibody production.  Blood 121:3484-3492, 2013.
• Yu M, Chen Y, He Y, Podd A, Fu G, Wright JA, Kleiman E, Khan WN, Wen R, and Wang D. Critical role of B cell lymphoma 10 in BAFF-regulated NF-kB activation and survival of anergic B cells.  J Immunol 189:5185-5193, 2012.
• Fu G, Chen Y, Wang D, and Wen R.  Important role of phospholipase Cgamma2 in T-cell receptor signal transduction and T-cell positive selection. J Immunol  189:2326-2332, 2012.
• Malherbe LP and Wang D. Tyrosine kinases enAbling adaptor molecules for chemokine-induced Rap1 activation in T cells.  Science Signal, 5:pe33, 2012.
• Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, and Wang D. STAT5 protein negatively regulates T follicular helper cell generation and function. J Biol Chem 287:11234-11239, 2012. 
• Gorjestani S, Yu M, Tang B, Zhang D, Wang D, and Lin X. Phospholipase Cγ2 (PLCγ2) Is Key Component in Dectin-2 Signaling Pathway, Mediating Anti-fungal Innate Immune Responses. J Biol Chem 286:43651-43659, 2011.
• Chen Y, Yu M, Dai X, Zogg M, Wen R, Weiler H, and Wang D. Critical role of Gimap5 in the survival of mouse hematopoietic stem and progenitor cells. J Exp Med 208:923-935; 2011.
• Wuerzberger-Davis S, Chen Y, Yang DT, Bates P, Ladell NC, Yu M, Podd A, Zeng H, Wen R, Wang D* and Miyamoto S*. Nuclear export of the NF-κB inhibitor IκBα is required for proper B cell and secondary lymphoid tissue formation. Immunity 34:188-200; 2011. *equal senior authorship
• Fu G, Chen Y, Yu M, Podd A, Schuman J, He Y, Di L, Yassai M, Haribhai D, North PE, Gorski J, Williams CB, Wang D, and Wen R. Phospholipase Cγ1 is essential for T-cell development, activation and tolerance. J Exp Med 207:309-318; 2010.
• Mueller H, Stadtmann A, Van Aken H, Wang D, Ley K, and Zarbock A. Tyrosine kinase Btk regulates E-selectin-mediated integrin activation & neutrophil recruitment by controlling phospholipase C (PLC)g2 and PI3Kg pathways. Blood 115:3118-3127; 2010.
• Schuman J, Chen Y, Podd A, Yu M, Liu H, Wen R, Chen ZJ, and Wang D. A critical role of TAK1 in B cell development and activation. Blood 113:4566-4574; 2009.
• Ohmori K, Luo Y, Jia Y, Nishida J, Wang Z, Bunting KD, Wang D, and Huang H. IL-3 induces basophil expansion in vivo by directing granulocyte-monocyte progenitors to differentiate into basophil lineage-restricted progenitors in the bone marrow and by promoting basophil/mast cell common progenitors to differentiate into basophils in the spleen. J Immunol 182:2835-2841; 2009.
• Chen Y, Yu M, Podd A, Wen R, Chrzanowska-Wodnicka M, White GC, and Wang D. A critical role of Rap1b in B cell trafficking and marginal zone B cell development. Blood 111:4627-4636; 2008.
• Schulteis RD, Chu H, Dai X, Chen Y, Edwards B, Haribhai D, Williams CB, Malarkannan S, Hessner MJ, Glisic-Milosavljevic S, Jana S, Kerschen EJ, Ghosh S, Wang D, et al. Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking gimap5. Blood 112:4905-4914; 2008.
• Chen Y, Wang X, Di L, Fu G, Chen Y, Bai L, Liu J, Feng X, McDonald JM, Michalek S, He Y, Yu M, Fu YX, Wen R, Wu H and Wang D. Phospholipase Cg2 mediates RANKL-stimulated lymph-node organogenesis and osteoclastogenesis. J Biol Chem 283:29593-29601; 2008.
• Zeng H, Chen Y, Yu M, Xue L, Gao X, Morris SW, Wang D, and Wen R. TCR-mediated activation of CD4+CD44hi T cells bypasses Bcl10. J Biol Chem 283:24392-24399; 2008.
• Bai L, Chen Y, He Y, Dai X, Lin X, Wen R, and Wang D. Phospholipase Cγ2 contributes to light chain gene activation and receptor editing. Mol Cell Biol 27:5957-5967; 2007.
• Blonska M, Pappu BP, Matsumoto R, Li H, Su B, Wang D, and Lin X. The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. Immunity 26:55-66; 2007.
• Malarkannan S, Regunathan J, Chu H, Chen Y, Zeng H, Kutlesa S, Wen R and Wang D. Activation of Bcl10 is essential for the signaling divergence of NKG2D-mediated cytotoxicity and cytokine generation in NK cells. J Immunol 179:3752-3762; 2007.
• Dai X, Chen Y, Di L, Podd A, Li G, Bunting KD, Hennighausen L, Wen R and Wang D. Stat5 is essential for early B cell development but not for B cell maturation and function. J Immunol 179:1068-1079; 2007.
• Shinners NP, Carlesso G, Castro I, Hoek K, Corn R, Woodland R, Scott ML, Wang D and Khan WN. Bruton’s tyrosine kinase mediates NF-kB activation and B cell survival by B cell activating factor of the TNF family. J Immunol 179:3872-3880; 2007.
• Misra RS, Russell JQ, Koenig A, Hinshaw-Makepeace JA, Wen R, Wang D, Huo H, Littman DR, Ferch U, Ruland J, Thome M and Budd RC. Caspase-8 and c-FLIPL associate in lipid rafts with NF-kB adaptors during T cell activation. J Biol Chem 282:19365-19374; 2007.
• Zhou M, McPherson L, Feng D, Song A, Dong C, Lyu SC, Zhou L, Shi X, Ahn YT, Wang D, Clayberger C and Krensky AM. KLF13 regulates T lymphocyte survival in vivo. J Immunol 178:5496-5504; 2007.
• Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, and Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358-9363; 2007.
• Chen Y, Pappu B, Zeng H, Xue L, Morris SW, Lin X, Wen R and Wang D. Bcl10 is essential for FceR-mediated degranulation and IL-6 production in mast cells. J Immunol 178:49-57; 2007.
• Wen R, Chen Y, Bai L, Fu G, Schuman J, Dai X, Zeng H, Yang C, Stephan RP, Cleveland JL, and Wang D. An essential role of phospholipase Cγ2 in early B cell development & Myc-mediated lymphomagenesis. Mol Cell Biol 26:9364–9376; 2006.
• Chen Y, Dai X, Haas AL, Wen R, and Wang D. Proteasome-dependent down-regulation of activated Stat5A in the nucleus. Blood 108:566-574; 2006.
• Dai X, Chen Y, Schuman J, Hua Z, Adamson JW, Wen R, and Wang D. Distinct roles of PI3K and PLCγ2 in B cell receptor-mediated signal transduction. Mol Cell Biol 26:88-99; 2006.
• Hoek KL, Antony P, Lowe J, Shinners N, Sarmah B, Wente SR, Wang D, Gerstein RM and Khan WN. Transitional B cell fate is associated with developmental stage-specific regulation of diacylglycerol and calcium signaling upon B cell receptor engagement. J Immunol 177:5405-5413; 2006.
• Regunathan J, Chen Y, Kutlesa S, Dai X, Bai L, Wen R, Wang D*, and Malarkannan S*. Differential and non-redundant roles of PLCγ2 and PLCγ1 in the terminal maturation of NK cells1. J Immunol 177:5365-5376; 2006. (*equal senior authorship).
• Xu W, Fukuyama T, Ney PA, Wang D, Rehg J, Boyd K, van Deursen JM, and Brindle PK. Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B-cells. Blood 107:4407-4416; 2006.
• Moriggl R, Sexl V, Kenner L, Duntsch C, Stangl K, Gingras S, Hoffmeyer A, Bauer A, Piekorz R, Wang D, et al. Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell 7:87-99; 2005.
• Regunathan J, Chen Y, Wang D and Malarkannan S. NKG2D-mediated NK cell cytotoxicity is regulated by Inhibitory Ly49 Receptors. Blood 105:233-240; 2005.
• Zhu M, Granillo O, Wen R, Yang K, Dai X, Wang D, and Zhang W. Negative regulation of lymphocyte activation by the adaptor protein LAX. J Immunol 174:5612-5619; 2005.
• Mutsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B, Chen Y, Wang D, Lin X. Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-kB activation. Immunity 23:575-585; 2005.
• Wen R, Chen Y, Schuman J, Yang S, Newman D, and Wang D. An important role of phospholipase Cγ1 in pre-B-cell development and allelic exclusion. EMBO J 23:4007-4017; 2004.
• Zhu Y, Chen L, Huang Z, Alkan S, Bunting KD, Wen R, Wang D, and Hua Huang. IL-5 primes Th2 cytokine-producing capacity in eosinophils through a STAT5-dependent mechanism. J Immunol 173:2918-2922; 2004.
• Xue L, Morris SW, Orihuela C, Tuomanen E, Cui X, Wen R, and Wang D. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nat Immunol 4:857-865; 2003.
• Wen R, Chen Y., Xue L, Schuman J, Yang S, Morris SW and Wang D.  Phospholipase Cg2 provides survival signals via Bcl-2 and A1 in different subpopulations of B cells. J Biol Chem 278:43654-43662; 2003.
• Chen Y, Wen R, Yang S, Schuman J, Zhang EE, Yi T, Feng GS and Wang D; 2003.. Identification of Shp-2 as a Stat5A phosphatase. J Biol Chem 278:16520-16527
• Cho MJ, Liu J, Pestina TI, Steward SA, Thomas DW, Coffman TM, Wang DaIIbb3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation. Blood 101:2646-2651; 2003., Jackson CW, and Gartner TK. The roles of
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• Wen R, Jou S, Chen Y, Hoffmeyer A and Wang D g2 is essential for specific functions of FceR and FcgR. J Immunol 169:6743-6752; 2002.. Phospholipase C
• Wang D, Feng J, Wen R, Marine JC, Sangster MS, Parganas E, Hoffmeyer A, Jackson CW, Cleveland JM, Murray PJ, and Ihle JN. Phospholipase Cγ2 is essential in the functions of B cell and several Fc Receptors. Immunity 13:25-35; 2000.
• Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, et al. Stat5 is essential for the myelo- and lympho-proliferative disease induced by TEL/JAK2 through regulation of Oncostatin M. Mol Cell 6:693-704; 2000.
• Wang D, Moriggl R, Stravopodis D, Carpino N, Marine JC, Teglund S, Feng J, and Ihle JN. A small amphipathic α-helical region is required for transcriptional activities and proteosome-dependent turnover of the tyrosine phosphorylated Stat5. EMBO J 19:392-399; 2000.
• Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, and Ihle JN. SOCS-1 deficiency causes a lymphocyte dependent perinatal lethality. Cell 98:609-616; 1999.
• Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima A, et al. SOCS-III is essential in the regulation of fetal liver erythropoiesis. Cell 98:617-627; 1999.
• Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:249-259; 1999.
• Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385-395; 1998.
• Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, et al. Stat5 A and B proteins have essential and non-essential, or redundant, roles in cytokine response. Cell 93:841-850; 1998.
• Wang D, Stravopodis D, Teglund S, Kitazawa J, and Ihle JN. Naturally occurring dominant negative variants of stat5. Mol Cell Biol 16:6141-6148; 1996.