Subramaniam Malarkannan, PhD Portrait

Subramaniam Malarkannan, PhD

Senior Investigator
Laboratory of Molecular Immunology and Immunotherapy
Blood Research Institute, BloodCenter of Wisconsin
 
Associate Professor
Division of Hematology and Oncology
Department of Medicine
Medical College of Wisconsin
 
Education and training
Postdoctoral Training
Immunology Division
Department of Molecular and Cellular Biology
UC Berkeley
 
Doctoral Training
Department of Immunology, PhD
Madurai Kamaraj University, Madurai, India
 
Contact Information
Phone: (414) 937-3812
Fax: (414) 937-6284

Immunobiology
My laboratory studies the development and functions of natural killer (NK ) cells.Our long term goal is to specifically augment the cytotoxic potentials of human NK cells and to successfully kill and clear tumor in patients.
 
Our current focus falls into three major categories:
  1. NKG2D- and NCR1-mediated signaling in NK cells
  2. NK cell-mediated anti-influenza responses in the lung
  3. Expression and functions of NK activating ligands during influenza infection (NO1)
NK cells are the major effector lymphocytes of innate immune system that defend against many forms of viral infections and tumor growth. NK cells are granular, bone marrow-derived lymphocytes capable of executing ‘natural cytotoxicity’ without prior sensitizations. NK cells bridge innate and adoptive immune responses through the secretion of a variety of cytokines and chemokines. Effector phase of NK cells are regulated by inhibitory and activating receptors. A signaling balance between the inhibitory and activating receptors determine the NK cell functions. NKG2D recognizes ‘induced-self’ ligands on tumor and virally infected cells. NCRs primarily recognize viral hemagglutinin (HA) on infected cells. Therefore, a better understanding of signaling events downstream of these two receptor systems in both murine and human NK cells is essential for successful formulation of NK-based cellular immunotherapies. Our long-term goals are to determine, evaluate and apply the molecular mechanisms that govern NK cell activation and its responses to viral and tumor challenges.


Activation through NKG2D and NCRs results in cytotoxic granule release, cytokine/chemokine generation and NK trafficking. NKG2D uses DAP10 and DAP12 to launch two signaling cascades. In the first, activated PTK phosphorylates YINM motif-bearing DAP10, which recruits PI3K-p85α. In the second, PTK phosphorylates the ITAM-containing DAP12 that triggers Syk and ZAP70, leading to the activation of PLC-γ2 pathway. Human NK has three NCRs while the murine NK express only NCR1 (NKp46). NCRs associate with CD3ζ and FcRγ(for NKp30 and NKp46), or DAP12 (for NKp44). Signaling events downstream of NCRs are yet to be determined. How these two activation receptor systems coordinate their activation cascades during viral clearance is of significant clinical relevance. At present, we are using multiple gene knockout mice to generate a detailed map of signaling events in NK cells.

NKG2D and NCRs are ubiquitously expressed on murine and human NK cells. NKG2D recognizes inducible self proteins as ligands while NCR interacts with influenza-derived HA proteins. Currently, nine murine and five human proteins have been defined as ligands for NKG2D receptor. These include ULBP (1-5), MIC (A & B) in human and H60 (a, b & c), Rae-1 (α, β, γ, δ & ε), Mult1 in mice. NKG2D ligands belong to non-classical MHC class I family and are inducible by multiple stress stimuli; therefore, defined as ‘induced-self’. These self-proteins are expressed due to pathological stimuli (such as influenza infection), share limited amino acid homology and form the molecular basis for NKG2D-mediated activation. During the course of identifying minor histocompatibility antigens, we determined the molecular identity of one of these ligands, H60a. This finding has opened newer avenues for our study. Currently, we are studying the molecular mechanisms by which the expression of these ligands is induced.

Grants
  • NCI, 1R01 CA179363, "Molecular signature of inflammation," Role: PI (03/10/2014 - 02/28/2019)
  • NIH-NIAID, R01 AI102893, "Molecular mechanisms of signaling co-ordination in innate lymphocytes," Role: PI (08/01/2013 - 07/31/2017)
  • Alex's Lemonade Stand Foundation, "Control of inflammation in genetically-modified lymphocytes," Role: PI (09/01/2013-08/30/2014)
  • Clinical and Translational Science Institute, "Cellular and adoptive immunotherapy using hematopoietic cell transplantation and NK cell infusion for the treatment of high risk pediatric and adult solid tumors: a Phase I/II Study," Role: Co-I (07/01/2012 - 06/30/2014)
  • American Cancer Society Pilot Research Grant, "NK cell immunotherapy in relapsed and refractory solid tumors," Role: Co-I (07/01/2012 - 06/30/2014)
  • MACC-Fund Novel Initiatives, "Cellular therapy using haploidentical donor NK cells," Role: PI (07/01/2012 - 06/30/2014)


Rajasekaran Kamalakannan, PhD

Research Scientist I

Kristina Schuldt
Research Technologist

Alex Abel
Graduate Student

Selected Publications
  • Rajasekaran K, Kumar P, Schuldt KM, Peterson EJ, Vanhaesebroeck B, Dixit V, Thakar MS, and Malarkannan S. 2013. Fyn-ADAP signaling via Carma1-Bcl10-MAP3K7 exclusively regulates inflammatory cytokine production in NK cells.  Nature Immunology, Vol 14:1127-1136.
  • Kumar P, Rajasekaran K, Palmer JM, Thakar MS, Malarkannan S. 2013. IL-22: An evolutionary missing-link authenticating the role of immune system in tissue regeneration. Journal of Cancer 4:57-65
  • Palmer MJ, Rajasekaran K, Thakar MS and Malarkannan S. 203. Clinical relevance of NK cell-mediated anti-microbial responses. Journal of Cancer 4:25-35
  • Kumar P, Rajasekaran K, Thakar MS, Ouyang W and Malarkannan S. 2013. IL-22 from conventional NK cells are epithelial regenerative and inflammation protective during influenza infection. Muscosal Immunology 1:69-82
  • Malarkannan S, Awasthi A, Rajasekaran K, Kumar P, Bartoszek A, Schuldt K, Manoharan N, Goldner N, Umhoefer C and Thakar MS. 2012. IQGAP1: A critical signal regulator in lymphocytes. J Immunol, 188:2057-63
  • Kumar P, Bartoszek A, Moran TM, Gorski J, Navidad N, Bhattacharyya S, Thakar MS and Malarkannan S. 2012. High-throughput rapid detection method for influenza viruses. JoVE, 60.3791/3623
  • Rajasekaran K, Chu H, Kumar P, Xia Y, Tinguely M, Samarakoon A, Kim TW, Li X, Thakar MS, Zhang J, Malarkannan S. 2011. TAK1 is a critical intermediate downstream of Carma1 in NK-mediated cytotoxicity and cytokine generation. JBC 286(36):31213-24
  • Kwun J, Malarkannan S, Burlingham W, and Knechtle SJ. 2011. Primary vascularization determines the immunodominance of mH-Ag during organ transplantation. J Immunol 187(8):3997-4006
  • Awasthi A, Samarakoon A, Chu H, Rajasekaran K, Quilliam L, Wodnicka M, White G, Malarkannan S. 2010. Rap1b facilitates NK cell functions via IQGAP1-mediated signalosomes. J Exp Med 207:1923-1938
  • Rajasekaran K, Xiong V, Fong L, Gorski J, and Malarkannan S. 2010. Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells. EPup. PloSOne
  • Guo H, Kumar P, and Malarkannan S. 2010. Evasion of natural killer cells by influenza virus. J Leuc Biol 89:1-6
  • Samarakoon A, Chu H, and Malarkannan S. 2009. Murine NKG2D Ligands: “Double, double toil and trouble.” Molecular Immunology 46:1011-1019
  • Guo H, Kumar P, Moran TM, Garcia-Sastre A, Zhou Y and Malarkannan S. 2009. The Functional Impairment of Natural Killer cells During Influenza Virus Infection. ‘Outstanding Observations’-Immunology and Cell biology 87:579-589
  • Guo H, Samarakoon A, Vanhaesebroeck B and Malarkannan S. 2008. The p110-delta isoform of PI 3-kinase plays a critical role in NK cell-mediated tumor killing and viral clearance. J. Exp Med. 205(10):2419-35
  • Schulteis RD, Chu H, Dai X, Chen Y, Edwards B, Haribhai B, Williams CB, Malarkannan S, Hessner MJ, Glisic-Milosavljevic S, Jana S, Kerschen EJ, Ghosh S, Wang D, Kwitek AE, Lernmark A, Gorski J, and Weiler H. 2008. Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking gimap5. Blood 112:4905-14
  • Chu H, Awasthi A, White GC, Chrzanowska-Wodnicka M and Malarkannan S. 2008. Rap1b Regulates B Cell Development, Homing, and T-Dependent Humoral Immunity. J. Immunol. 181(5):3373-83
  • Awasthi A, Chu H, Kutlesa S, Wang D and Malarkannan S. 2008. p85a subunit of PI3K plays a pivotal role in the cytokine generation in NK cells. Genes Immun. 9(6):522-35
  • Reinbold C and Malarkannan S, 2008. Recognition of allo-peptide is governed by novel anchor imposition and limited variations in TCR contact residues. Mol. Immunol. 45:1318-26
  • Malarkannan S, Regunathan J, Chu H, Kutlesa S, Chen Y, Zeng H, Wen R, and Wang D, 2007. Bcl10 plays a pivotal role in the NK cell-mediated cytotoxicity and cytokine generation. Journal of Immunology 179(6):3752-62.
  • Regunathan J, Chen Y, Kutlesa S, Dai X, Bai L, Wen R, Wang D, and Malarkannan S, 2006. Differential and non-redundant roles of PLCγ2 and PLCγ1 in the terminal maturation of NK cells. Journal of Immunology 177(8):5365-76.
  • Malarkannan S, 2006. Altered-Balance: Inhibitory Ly49 receptors regulate NKG2D-mediated NK cell functions. Seminars in Immunology 18:3.
  • Malarkannan S, 2006. NK cell development and function: Missing-self revisited. Editorial, Seminars in Immunology 18:3.
  • Malarkannan S, 2005. Minor histocompatibility antigens: Time for a paradigm shift? Transplantation Reviews 19:1-19.
  • Regunathan J, Chen Y, Wang D, Malarkannan S, 2005. NKG2D-mediated NK cell function is regulated by inhibitory Ly49 receptors. Blood 105:233-240.
  • Malarkannan S, Regunathan J, Tranchita AM, 2005. Minor histocompatibility antigens: Molecular targets for immunomodulation in tissue transplantation and tumor therapy. Clinical and Applied Immunology Reviews 5:95-109.
  • Schwab SR, Shugart JA, Horng T, Malarkannan S, Shastri N, 2004. Unanticipated antigens: Translation initiation at CUG with leucine. PloS Biology 2:1774-1784, 2004.
  • Malarkannan S and Pooler LM, 2004. Minor H Antigens: Molecular Barriers for successful Organ Transplantations. Ed: Drs D. Wilkes and W. Burlingham., in ‘Immunobiology of Organ Transplantation’, Chapter 7, Kluwer/Plenum Press.
  • Luedtke B, Tranchita A, Reinbold C, Choi E Y, Roopenian D, and Malarkannan S, 2003. A single amino acid polymorphism is the Emp-3 gene defines immunodominant CTL responses directed to the minor histocompatibility antigen, H4 Immunogenetics-55: 284-295.
  • Eun Young Choi E Y, Christianson G J, Malarkannan S, Joyce S, Roopenian, D, 2002. Real-time T cell Profiling Identifies H60 As a Major Minor Histocompatibility Antigen in Murine Graft-vs-Host Disease. Blood 100:4259-4264
  • Malarkannan S, 2002, Minor Histocompatibility Antigens: Non-MHC Polymorphic Barriers Against Successful Transplant Acceptance (Invited Review article-in preparation for Current Opinion in Organ Transplantation, Vol7: 3.
  • Mendoza LM, Malarkannan S and Shastri N. 2001 Identification of CD8+ T-cell-stimulating antigen genes in cDNA libraries Methods Mol Biol. 156:255-63
  • Malarkannan S, Mendoza LM, and Shastri, N. 2001 Generation and analysis of LacZ inducible T cell hybrids Methods Mol Biol. 156:265-72
  • Eun Young Choi E Y, Christianson G J, Sproule T J, Yoshimura Y, Malarkannan S, Shastri N, Joyce S, Roopenian, D, 2001. Quantitative analysis of the immune response to mouse non-MHC transplantation antigens in vivo: the H60 histocompatibility antigen, dominates over all others. J. Immunol.166: 4370-4379
  • Malarkannan S, Horng T, Eden P, Gonzalez F, Shih P, Brouwenstijn N, Roopenian D, and Shastri N, 2000. Differences that matter: The major cytotoxic T cell stimulating minor histocompatibility antigens. Immunity 13:4
  • Malarkannan S, Horng T, Shih P and Shastri, N. 1999 Presentation of out-of-frame peptide/MHC class I complexes by a novel translation initiation mechanism. Immunity, 10:681-690
  • Malarkannan S, Shih P, Eden P, Horng T, Zuberi A, Christianson G, Roopenian D, and Shastri N. 1998. The Molecular and Functional Characterization of a dominant minor H antigen, H60 J. Immunol. 161:3501-09
  • Malarkannan S, Serwold T, Nguyen V, Sherman LA, and Shastri N. 1996 The mouse mammary tumor virus env gene is the source of a CD8+ T-cell stimulating peptide presented by a major histocompatibility complex class I molecule in a murine thymoma. Proc. Natl. Acad. Sci. (USA) 93:13991-96
  • Malarkannan S, Gonzalez F, Nguyen V, Adair G, and Shastri N. 1996. Alloreactive CD8+ T-cells can rmajor histocompatibility complex class I molecule to alloreactive T-cells. J. Exp. Med. 182:1739-50
  • Malarkannan S, Goth S, Buchholz DR, and Shastri N. 1995 The role of MHC class I molecules in the generation of endogenous peptide/MHC complexes. J. Immunol, 154: 585-98

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