Immunologic Research

, Volume 50, Issue 2–3, pp 159–174 | Cite as

Role of TNF superfamily ligands in innate immunity

  • Nikola L. VujanovicEmail author


Natural killer (NK) cells and dendritic cells (DCs) are essential effector cells of the innate immune system that rapidly recognize and eliminate microbial pathogens and abnormal cells, and induce and regulate adaptive immune functions. While NK cells express perforin and granzymes in the lysosomal granules and transmembrane tumor necrosis factor superfamily ligands (tmTNFSFL) on the plasma membrane, DCs express only tmTNFSFL on the plasma membrane. Perforin and granzymes are cytolytic molecules, which NK cells use to mediate a secretory/necrotic killing mechanism against rare leukemia cell targets. TNFSFL are pleiotropic transmembrane molecules, which can mediate a variety of important functions such as apoptosis, development of peripheral lymphoid tissues, inflammation and regulation of immune functions. Using tmTNFSFL, NK cells and DCs mediate a cell contact-dependent non-secretory apoptotic cytotoxic mechanism against virtually all types of cancer cells, and cross talk that leads to polarization and reciprocal stimulation and amplification of Th1 type cytokines secreted by NK cells and DCs. In this paper, we review and discuss the supporting evidence of the non-secretory, tmTNFSFL-mediated innate mechanisms of NK cells and DCs, their roles in anticancer immune defense and potential of their modulation and use in prevention and treatment of cancer.


TNF superfamily ligands TNF superfamily receptors NK cells Dendritic cells Cytotoxicity Cross talk 



I am grateful to the following previous and current members of my laboratory for their contributions in the presented studies: Bratislav Janjic, Ganwei Lu, Jelena Janjic, Alexei Pimenov and Dejan Baskic (studies of NK cell and DC apoptotic tumoricidal activity); Jun Xu, Valeria Makarenkova, Petar Popovic, Jennifer Liberatore-Tan, Lisheng Ge, Ayan Chakrabarti, Michael Magee, Andrea Sobo-Vujanovic, Toshie Yoneyama and Sebnem Unlu (studies of NK cell/DC cross talk). I am also indebted to the following collaborators: Lazar Vujanovic, Lisa Butterfield, Sigeki Nagashima, Roberto Giorda, Theresa Whiteside, Ronald Herberman, Simon Watkins, Nebojsa Arsenijevic, Per Basse, Eugene Myers, Susan Gollin, Jennifer Hunt and Walter Storkus. In addition, I am obliged to David Szymkowski (XENCOR, Monrovia, CA) who has generously provided us with dominant negative TNF (DN-TNF, XPro1595 and XENP550) reagents. This study was supported by research funding from the National Institute of Health grants I-PO DE13059, RO1 DE14775, RO1 DE17150 and the University of Pittsburgh Cancer Institute and the Henry L. Hillman Foundation to N.L.V.


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Departments of Pathology and ImmunologyUniversity of PittsburghPittsburghUSA
  2. 2.Hillman Cancer CenterUniversity of PittsburghPittsburghUSA

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