PhD, 1993, University of Toronto
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.
For Further information, see K. Narayan and J. Kang, 2007 Curr. Opin. Immunol.
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.
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.