This proposal describes a 5-year research plan focusing on the proximal signaling complexes that are formed downstream of natural killer (NK) cell activating receptors and how signaling pathways leading from these complexes affect NK cell effector function and development. NK cells are innate immune cells that defend the host from intracellular pathogens and tumors. Regulation of NK cell activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors (e.g., Ly49 family members), which allow NK cells to achieve self tolerance. How the precise signaling pathways leading from NK cell activating receptors contribute to mature NK cell effector function and inhibitory receptor acquisition during development are not well understood. Signaling through activating immunoreceptors relies on the formation of a proximal multimolecular complex nucleated by the adaptor protein SH2 containing leukocyte protein of 76kD (SLP-76). Our preliminary data support an important role for SLP-76 in activating receptor-mediated NK cell effector signal transduction, which is critical for NK cell effector function and Ly49 receptor acquisition. In addition, our data suggest that NK cells also use an alternative mechanism that may be different from other hematopoietic cell types to localize SLP-76 to the plasma membrane and to initiate signal transduction. This alternative signal transduction pathway leading from SLP-76 may be important during NK cell development for the acquisition of Ly49 receptors. In this proposal, we hypothesize that SLP-76 mediates multiple signal transduction pathways downstream of NK cell activating receptors, which play differential roles in NK cell effector function and in the acquisition of Ly49 receptors. Our research plan starts with an examination of how proximal signaling complexes involving SLP-76 are formed in NK cells downstream of activating receptors. We will then examine how these signal transduction pathways contribute to the different NK cell effector functions and to NK cell acquisition of Ly49 receptors. The experiments described in this proposal will yield insight into the precise signal transduction pathways downstream of activating receptors in NK cells, which is essential for our understanding of how NK cells are activated in the periphery and achieve self tolerance through expression of Ly49 receptors. This information will allow us to devise novel strategies to modulate NK cell responses in multiple disease settings. Our expertise in signal transduction and NK cell biology together with our expert consultants (Drs. Jordan Orange, Tobias Baumgart, and Yoji Shimizu), and the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed research plan. Thus, we believe that we are uniquely equipped with the tools/reagents and expertise to investigate this important aspect of NK cell biology.

Public Health Relevance

Natural killer (NK) cells belong to the innate immune system and play a vital role in defending the host from intracellular pathogens and tumors. The goal of this proposal is to investigate how signal transduction pathways through activating receptors affect NK cell effector function and Ly49 receptor acquisition during development. Further understanding of how NK cells are activated in the periphery and achieve self tolerance through expression of Ly49 receptors will allow us to devise novel strategies to control NK cell responses in multiple disease settings.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL107589-04
Application #
8644134
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Thomas, John
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bagawath-Singh, Sunitha; Staaf, Elina; Stoppelenburg, Arie Jan et al. (2016) Cytokines Induce Faster Membrane Diffusion of MHC Class I and the Ly49A Receptor in a Subpopulation of Natural Killer Cells. Front Immunol 7:16
Singh, Brenal K; Kambayashi, Taku (2016) The Immunomodulatory Functions of Diacylglycerol Kinase ζ. Front Cell Dev Biol 4:96
Yang, Enjun; Singh, Brenal K; Paustian, Amanda M Schmidt et al. (2016) Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function. J Immunol 197:934-41
Freund, Jacquelyn; May, Rebecca M; Yang, Enjun et al. (2016) Activating Receptor Signals Drive Receptor Diversity in Developing Natural Killer Cells. PLoS Biol 14:e1002526
Schmidt, Amanda M; Lu, Wen; Sindhava, Vishal J et al. (2015) Regulatory T cells require TCR signaling for their suppressive function. J Immunol 194:4362-70
Karimi, Mobin A; Bryson, Jerrod L; Richman, Lee P et al. (2015) NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT. Blood 125:3655-63
Basiaga, Matthew L; Weiss, Pamela F; Behrens, Edward M (2015) BIRC4 Mutation: An Important Rare Cause of Uveitis. J Clin Rheumatol 21:444-7
Reshef, Ran; Huffman, Austin P; Gao, Amy et al. (2015) High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning. J Clin Oncol 33:2392-8
Arumugam, Vidhyalakshmi; Bluemn, Theresa; Wesley, Erin et al. (2015) TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β. J Leukoc Biol 98:703-12
Huang, Yanping; Clarke, Fiona; Karimi, Mobin et al. (2015) CRK proteins selectively regulate T cell migration into inflamed tissues. J Clin Invest 125:1019-32

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