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    Joonsoo Kang PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPathology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-2759
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Overview 
        Narrative

        Academic Background

        PhD, 1993, University of Toronto

        Dr. Joonsoo Kang

        Overall research theme

        Lymphocytes guard against pathogens to maintain an organism’s integrity and health. However, there are some costs to this protection. Lymphocytes are prone to transformation, and leukemia and lymphomas can arise. Lymphocytes can also cause harm to self, and the frequency of autoimmune disease is increasing alarmingly among developed western nations, which comes with immense social costs. By understanding how these diseases develop we can formulate new, specific therapies that will have minimal side effects. In our lab, we study the normal process of T lymphocyte development to understand how and why things go wrong. We are also exploring how T cells function to maintain tolerance to self, poised to react only to disease-causing foreign pathogens. The morphogens WNT and TGFb represent a common theme in our studies. These molecules and the pathways they regulate are absolutely essential for T cell development, homeostasis and function, yet only limited details about how they modulate immunity exist. Our goals are to investigate in depth the genetic and cellular components of WNT and TGFb signaling that control a T cell’s life, from its birth to its death.

        What we study currently

        T cell lineage commitment: One central research aim in my laboratory is to decipher the molecular basis of T cell lineage commitment. As a backdrop, this issue is intimately linked to the nature of lineage fate decision processes in many other developmental systems. Understanding this process is central to deciphering how cancers of lymphocytes develop. Currently we are investigating how a bipotential T cell precursor in the thymus gives rise to two distinct types of T cells: gd and ab T cells. We have provided evidence for the existence of two lineage-biased precursor populations prior to the developmental stage at which T cell antigen receptors (TCRs) are expressed. These lineage-restricted precursor populations differentially express the receptor for interleukin-7, a critical growth and differentiation factor for T and B lymphocyte development, and are predicted to be molecularly heterogeneous. We are identifying novel genes and genetic pathways that are important for T cell lineage commitment by comparing the global gene expression profiles of all known developmental intermediates in the hematopoietic lineage (www.Immgen.org). We are investigating functions of some of these genes in transgenic and/or knock-out animal model systems, focusing especially on the TCF1/SOX13 axis that modulates WNT signaling. Our goal is to systematically identify the molecular pathways dictating ab versus gd T cell differentiation (www.ImmGen.org; Heng, T., Painter, M., The Immunological Genome Project Consortium, 2008 Nat. Immunol. 9:1091), understand how the pathways are modified by extrinsic cues such as cytokines and morphogens, and identify the consequences for the organism when they are dysregulated.

        T cell homeostasis: Another central research focus in my laboratory is to uncover the mechanisms involved in regulating T cell activation and homeostasis. In particular, we are interested in defining the dynamic role of T cell costimulatory and coinhibitory molecules. The T cell molecule CD28 is the primary costimulatory molecule for naïve T cells, whereas the CD28 homologue CTLA-4 inhibits T cell activation. A delicate balance between CD28 and CTLA-4 signaling dictates effective immunity: A drastic pivot in favor of CD28 results in overt T cell activation and autoimmunity. An opposite tilt results in ineffective immune responses to pathogens and infectious diseases. Drugs that modulate this balance are currently in clinics to treat autoimmune diseases and to elicit hyper-responses against tumor cells. As such, it is crucial that we understand how CD28 and CTLA-4 function in vivo.

        A crucial role for CTLA-4 in T cell responses and homeostasis was demonstrated in mice with a genetically induced deficiency in CTLA-4. We have shown that these mice develop a rapid-onset, fatal, polyclonal T cell lymphoproliferative disorder, due to the unrestrained activation of CD4+ T cells against self-tissues in vivo. Currently we are examining the integration of the TCR, CD28 and CTLA-4-mediated signals in CD4+ and CD8+ T cell subsets using TCR transgenic mice and mice deficient in costimulation and/or antigen presentation. Utilizing mice lacking CTLA-4 as a model of systemic autoimmunity, we are also examining the cellular and molecular requirements necessary to control potentially self-reactive T cells in vivo, with the goal of understanding the role of costimulatory molecules in tolerance induction and ultimately, to identify novel gene products necessary for the maintenance of T cell homeostasis.

        We have determined that CTLA-4 has a dual function to prevent autoimmunity. First, the regulatory T (Treg) cell subset (FOXP3+) employs CTLA-4 to maintain systemic quiescence of naïve T cells against self antigens in trans (conventional T cell extrinsic). Second, on conventional effector T cells, it prevents aberrantly activated T cells from entering non-lymphoid organs (conventional T cell intrinsic). By understanding the biochemical basis of CTLA-4 function we have been able to identify drugs to control the lymphoproliferative disease of CTLA-4-deficient mice. This result offers novel targets of immunotherapy to treat organ specific autoimmune diseases such as Type 1 diabetes and Multiple Sclerosis.

        Finally, given the importance of Treg cells in maintaining T cell homeostasis and tolerance to self, and its functional link to CTLA-4, we are investigating the mechanism of function of TGFb. This morphogen is the immunosuppressive cytokine responsible for Treg cell maintenance that turns on FOXP3, which in turn induces CTLA-4, as well as having direct effects on conventional T cells. By understanding how TGFb signals uniquely in a context-dependent manner to regulate T cell activation and effector function we will provide insights into Treg cell effector mechanisms and the programming of TGFb responsiveness in developing T cells.

        AlphaBeta

        For Further information, see K. Narayan and J. Kang, 2007 Curr. Opin. Immunol.

        Key References:

        Review articles

        1. Narayan, K. and J. Kang (2007) Molecular events regulating gd versus ab T cell lineage commitment: Old suspects, new players, and different game plans. Curr Opin. Immunol. 19:169-175.

        2. Melichar, H. J. and J. Kang (2007) Integrated morphogen signal inputs in gd versus ab T-cell differentiation. Immunol. Rev. 215:32-45

        3. Chambers, C. A., M. S. Kuhns, J. Egen and J. P. Allison. (2001) CTLA-4-meditaed inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Ann. Rev. Immunol. 19: 565-594.

        Research articles

        1. N. Malhotra, K. Narayan, O. Cho, K.E. Sylvia, C. Yin, H. Melichar, V. Lefebvre, L. J. Berg and J. Kang. (2013) A network of High Mobility Group box transcription factors programs innate IL-17 production. Immunity.

        2. Narayan K, Sylvia KE, Malhotra N, Yin CC, Martens G, Vallerskog T, Kornfeld H, Xiong N, Cohen NR, Brenner MB, Berg LJ, Kang J. Intrathymic programming of effector fates in three molecularly distinct gd T cell subtypes. Nat Immunol. 2012 May; 13(5):511-8.

        3. Friedline, R. H., D. S. Brown, H. Nguyen, H. Kornfeld, J. Lee, Y. Zhang, S. D. Der, J. Kang and C. A. Chambers (2009) CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 206:421-34.

        4. Melichar, H. J., K. Narayan, S. D. Der, Y. Hiraoka, N. Gardiol, G. Jeannet, W. Held, C. A. Chambers and J. Kang (2007) Regulation of gd versus ab T lymphocyte differentiation by the transcription factor SOX13. Science 315:230-233.

        5. Zhao, H., H. Nguyen and J. Kang. (2005) IL-15 controls the generation of the restricted TCR repertoire of gd intestinal intraepithelial lymphocytes. Nature Immunol 6:1263-1271.

        6. Chambers, C. A., J. Kang, Y. Wu, W. Held, D. H. Raulet, and J. P. Allison (2002) Lympho-proliferation in CTLA-4-deficient mice is ameliorated by the inhibitory NK receptor Ly49A. Blood, 99:4509-4516.

        7. Kang, J., A. Volkmann and D. H. Raulet. (2001) Evidence that gd/ab T cell lineage commitment is independent of TCR signaling. J. Exp. Med. 193: 689-698.



        Rotation Projects

        Potential Rotation Projects

        1. SOX proteins in the maintenance of mucosal tissue integrity and innate immunity. There are ~20 Sox genes in mammals. Although the prototypic SOX-related proteins, SRY (Sex-determining gene on Y chromosome) and TCF/LEF are reasonably well characterized, very little is known about the relevance of SOX proteins in lymphocyte development and function. We have discovered that some SOX proteins can regulate the WNT/Wingless signaling cascade, a central morphogenetic pathways specifying cell fate in all organisms whose aberrant activity leads to tumourigenesis. Importantly, expression of specific combinations of Sox genes is lymphocyte subset-specific, temporally and spatially. Our results so far strongly indicate that Sox genes are important regulators of multiple lymphocyte subsets, in part by opposing WNT signaling. An impediment to advances in understanding Sox gene functions has been that they are critical for embryonic development and mutations lead to early lethality. We have therefore embarked on generating conditional KO mice of various Sox genes and their cofactors that we postulate are centrally involved in lymphocyte differentiation and function. A few rotation projects are available to analyze these newly derived mouse models, both at the level of cellular and molecular analysis of lymphocyte development and single-cell tracking of specific Sox gene expressing cells in vivo. These mice have defects in mucosal tissue barrier functions and often exhibit aberrant inflammatory responses in the skin that can model human skin diseases such as psoriasis and dermatitis.

        a. analysis of Sox13 reporter mice

        b. analysis of Sox4-deficient mice for innate lymphocyte developmental defects

        c. analysis of spontaneous skin inflammation in mice lacking dermal innate IL-17 producers

        d. analysis of global chromatin docking of HMG TFs in ex vivo T cells

        e. comparative analysis of global gene regulation and gene networks across all hematopoietic cells


        2. Testing small molecule compounds to treat organ-specific T cell-mediated autoimmunity in mice (e.g. Type I Diabetes, colitis and the mouse model of multiple sclerosis).

        3. Analysis of mice with novel mutations in TGFb signaling to investigate the role of TGFb in regulating self-destructive T cells.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Kang for additional details.

        Postdoctoral positionsstarting in Apr 2013 for studies of the molecular mechanisms of T cell lineagecommitment, innate lymphoid cell and innate-like T cell development, generegulatory networks underpinning the hematopoietic system (ImmGen.org), orself-reactive T cell trafficking to tissues in organ-specific autoimmunity.Applicants must have a record of accomplishment in immunology or developmentalbiology with technical fluency in molecular biology, animal model generationand analysis, gene expression analysis and/or intravital imaging. Send a letterof interest, CV and names of three references to: Joonsoo Kang, Ph. D., E-mail(preferred): joonsoo.kang@ umassmed.edu. Dept. of Pathology, The Albert ShermanCenter (http://www.umassmed.edu/shermancenter/index.aspx)at Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA01655. Regrettably, due to the large number of applicants, those without the specified qualifications will not be considered and no acknowledgement of receipt will be sent.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Kapoor VN, Shin HM, Cho OH, Berg LJ, Kang J, Welsh RM. Regulation of Tissue-Dependent Differences in CD8+ T Cell Apoptosis during Viral Infection. J Virol. 2014 Sep 1; 88(17):9490-503.
          View in: PubMed
        2. Prince AL, Watkin LB, Yin CC, Selin LK, Kang J, Schwartzberg PL, Berg LJ. Innate PLZF+CD4+ aß T Cells Develop and Expand in the Absence of Itk. J Immunol. 2014 Jul 15; 193(2):673-87.
          View in: PubMed
        3. Jain N, Miu B, Jiang JK, McKinstry KK, Prince A, Swain SL, Greiner DL, Thomas CJ, Sanderson MJ, Berg LJ, Kang J. CD28 and ITK signals regulate autoreactive T cell trafficking. Nat Med. 2013 Dec; 19(12):1632-7.
          View in: PubMed
        4. Mingueneau M, Kreslavsky T, Gray D, Heng T, Cruse R, Ericson J, Bendall S, Spitzer MH, Nolan GP, Kobayashi K, von Boehmer H, Mathis D, Benoist C. The transcriptional landscape of aß T cell differentiation. Nat Immunol. 2013 Jun; 14(6):619-32.
          View in: PubMed
        5. Malhotra N, Kang J. SMAD regulatory networks construct a balanced immune system. Immunology. 2013 May; 139(1):1-10.
          View in: PubMed
        6. Jojic V, Shay T, Sylvia K, Zuk O, Sun X, Kang J, Regev A, Koller D. Identification of transcriptional regulators in the mouse immune system. Nat Immunol. 2013 Jun; 14(6):633-43.
          View in: PubMed
        7. Malhotra N, Narayan K, Cho OH, Sylvia KE, Yin C, Melichar H, Rashighi M, Lefebvre V, Harris JE, Berg LJ, Kang J. A network of high-mobility group box transcription factors programs innate interleukin-17 production. Immunity. 2013 Apr 18; 38(4):681-93.
          View in: PubMed
        8. Yin CC, Cho OH, Sylvia KE, Narayan K, Prince AL, Evans JW, Kang J, Berg LJ. The Tec kinase ITK regulates thymic expansion, emigration, and maturation of ?d NKT cells. J Immunol. 2013 Mar 15; 190(6):2659-69.
          View in: PubMed
        9. Cohen NR, Brennan PJ, Shay T, Watts GF, Brigl M, Kang J, Brenner MB. Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nat Immunol. 2013 Jan; 14(1):90-9.
          View in: PubMed
        10. Narayan K, Sylvia KE, Malhotra N, Yin CC, Martens G, Vallerskog T, Kornfeld H, Xiong N, Cohen NR, Brenner MB, Berg LJ, Kang J. Intrathymic programming of effector fates in three molecularly distinct ?d T cell subtypes. Nat Immunol. 2012 May; 13(5):511-8.
          View in: PubMed
        11. Kang J, Coles M. IL-7: the global builder of the innate lymphoid network and beyond, one niche at a time. Semin Immunol. 2012 Jun; 24(3):190-7.
          View in: PubMed
        12. Yoon KS, Strycharz JP, Baek JH, Sun W, Kim JH, Kang JS, Pittendrigh BR, Lee SH, Clark JM. Brief exposures of human body lice to sublethal amounts of ivermectin over-transcribes detoxification genes involved in tolerance. Insect Mol Biol. 2011 Dec; 20(6):687-99.
          View in: PubMed
        13. Jin Y, Xia M, Saylor CM, Narayan K, Kang J, Wiest DL, Wang Y, Xiong N. Cutting edge: Intrinsic programming of thymic ?dT cells for specific peripheral tissue localization. J Immunol. 2010 Dec 15; 185(12):7156-60.
          View in: PubMed
        14. Malhotra N, Robertson E, Kang J. SMAD2 is essential for TGF beta-mediated Th17 cell generation. J Biol Chem. 2010 Sep 17; 285(38):29044-8.
          View in: PubMed
        15. Jeannet G, Boudousquié C, Gardiol N, Kang J, Huelsken J, Held W. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc Natl Acad Sci U S A. 2010 May 25; 107(21):9777-82.
          View in: PubMed
        16. Narayan K, Kang J. Disorderly conduct in gammadelta versus alphabeta T cell lineage commitment. Semin Immunol. 2010 Aug; 22(4):222-7.
          View in: PubMed
        17. Jain N, Nguyen H, Chambers C, Kang J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci U S A. 2010 Jan 26; 107(4):1524-8.
          View in: PubMed
        18. Jain N, Nguyen H, Friedline RH, Malhotra N, Brehm M, Koyanagi M, Bix M, Cooper JA, Chambers CA, Kang J. Cutting edge: Dab2 is a FOXP3 target gene required for regulatory T cell function. J Immunol. 2009 Oct 1; 183(7):4192-6.
          View in: PubMed
        19. Felices M, Yin CC, Kosaka Y, Kang J, Berg LJ. Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo. Proc Natl Acad Sci U S A. 2009 May 19; 106(20):8308-13.
          View in: PubMed
        20. Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J, Zhang Y, Appleby M, Der SD, Kang J, Chambers CA. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med. 2009 Feb 16; 206(2):421-34.
          View in: PubMed
        21. Stavnezer J, Kang J. The surprising discovery that TGF beta specifically induces the IgA class switch. J Immunol. 2009 Jan 1; 182(1):5-7.
          View in: PubMed
        22. Liang H, Coles AH, Zhu Z, Zayas J, Jurecic R, Kang J, Jones SN. Noncanonical Wnt signaling promotes apoptosis in thymocyte development. J Exp Med. 2007 Dec 24; 204(13):3077-84.
          View in: PubMed
        23. Coles AH, Liang H, Zhu Z, Marfella CG, Kang J, Imbalzano AN, Jones SN. Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis. Cancer Res. 2007 Mar 1; 67(5):2054-61.
          View in: PubMed
        24. Narayan K, Kang J. Molecular events that regulate alphabeta versus gammadelta T cell lineage commitment: old suspects, new players and different game plans. Curr Opin Immunol. 2007 Apr; 19(2):169-75.
          View in: PubMed
        25. Melichar H, Kang J. Integrated morphogen signal inputs in gammadelta versus alphabeta T-cell differentiation. Immunol Rev. 2007 Feb; 215:32-45.
          View in: PubMed
        26. Melichar HJ, Narayan K, Der SD, Hiraoka Y, Gardiol N, Jeannet G, Held W, Chambers CA, Kang J. Regulation of gammadelta versus alphabeta T lymphocyte differentiation by the transcription factor SOX13. Science. 2007 Jan 12; 315(5809):230-3.
          View in: PubMed
        27. Zhao H, Nguyen H, Kang J. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nat Immunol. 2005 Dec; 6(12):1263-71.
          View in: PubMed
        28. Kang J, DiBenedetto B, Narayan K, Zhao H, Der SD, Chambers CA. STAT5 is required for thymopoiesis in a development stage-specific manner. J Immunol. 2004 Aug 15; 173(4):2307-14.
          View in: PubMed
        29. Kang J, Der SD. Cytokine functions in the formative stages of a lymphocyte's life. Curr Opin Immunol. 2004 Apr; 16(2):180-90.
          View in: PubMed
        30. Chambers CA, Kang J, Wu Y, Held W, Raulet DH, Allison JP. The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor. Blood. 2002 Jun 15; 99(12):4509-16.
          View in: PubMed
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