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Academic Background

University of Toronto and University of California, Berkeley

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 in 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. Conversely, new drugs that can hyperactivate T cells may enhance efficacy of T cell immunotherpies against cancer. 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 and to survery for cancer cells. 

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. 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) and by single cell transcriptomics. 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 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 (so called checkpoint inhibitors along with PD-1) 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.

Post Docs

 

Postdoctoral positionsstarting in March 2019 for studies of the gene regulatory networks underpinning the hematopoietic system (ImmGen.org), self- or tumor-reactive T cell trafficking to tissues in organ-specific autoimmunity and tumor surveillance, respectively. 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. 

 

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.

One or more keywords matched the following items that are connected to Kang, Joonsoo
Item TypeName
Academic Article The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor.
Academic Article STAT5 is required for thymopoiesis in a development stage-specific manner.
Academic Article Regulation of gammadelta versus alphabeta T lymphocyte differentiation by the transcription factor SOX13.
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Academic Article Cutting edge: Dab2 is a FOXP3 target gene required for regulatory T cell function.
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Academic Article Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells.
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Academic Article A network of high-mobility group box transcription factors programs innate interleukin-17 production.
Academic Article The transcriptional landscape of ?? T cell differentiation.
Academic Article Cytokine functions in the formative stages of a lymphocyte's life.
Academic Article Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes.
Academic Article Integrated morphogen signal inputs in gammadelta versus alphabeta T-cell differentiation.
Academic Article Molecular events that regulate alphabeta versus gammadelta T cell lineage commitment: old suspects, new players and different game plans.
Academic Article Noncanonical Wnt signaling promotes apoptosis in thymocyte development.
Academic Article CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance.
Academic Article Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo.
Academic Article Disorderly conduct in gammadelta versus alphabeta T cell lineage commitment.
Academic Article Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory.
Academic Article Cutting edge: Intrinsic programming of thymic ??T cells for specific peripheral tissue localization.
Academic Article Intrathymic programming of effector fates in three molecularly distinct ?? T cell subtypes.
Academic Article The Tec kinase ITK regulates thymic expansion, emigration, and maturation of ?? NKT cells.
Academic Article Identification of transcriptional regulators in the mouse immune system.
Concept Receptors, Antigen, T-Cell, alpha-beta
Concept Receptors, NK Cell Lectin-Like
Concept Cell Lineage
Concept Receptors, Antigen, T-Cell
Concept Cell Communication
Concept Cell Survival
Concept Dendritic Cells
Concept CHO Cells
Concept Multipotent Stem Cells
Concept Cell Differentiation
Concept Cell Line, Transformed
Concept Bone Marrow Cells
Concept Cell Movement
Concept Cells, Cultured
Concept T Cell Transcription Factor 1
Concept Cell Separation
Concept Receptors, Antigen, T-Cell, gamma-delta
Concept Natural Killer T-Cells
Concept Cell Proliferation
Concept Hematopoietic Stem Cells
Concept Genes, T-Cell Receptor gamma
Concept Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
Concept Stem Cell Factor
Concept NK Cell Lectin-Like Receptor Subfamily A
Concept Cell Migration Inhibition
Concept Cell Transformation, Neoplastic
Concept Th2 Cells
Concept Cell Line
Concept Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
Concept Killer Cells, Natural
Concept Cell Line, Tumor
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Academic Article Neonatal-derived IL-17 producing dermal ?? T cells are required to prevent spontaneous atopic dermatitis.
Concept Th17 Cells
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