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Jimmunol.1600667.Full-Text.Pdf Lack of Both Nucleotide-Binding Oligomerization Domain−Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death This information is current as of October 2, 2021. Sashi G. Kasimsetty, Alana A. Shigeoka, Andrew A. Scheinok, Amanda L. Gavin, Richard J. Ulevitch and Dianne B. McKay J Immunol published online 26 June 2017 http://www.jimmunol.org/content/early/2017/06/24/jimmun Downloaded from ol.1600667 Supplementary http://www.jimmunol.org/content/suppl/2017/06/24/jimmunol.160066 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 26, 2017, doi:10.4049/jimmunol.1600667 The Journal of Immunology Lack of Both Nucleotide-Binding Oligomerization Domain–Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death Sashi G. Kasimsetty,* Alana A. Shigeoka,* Andrew A. Scheinok,* Amanda L. Gavin,† Richard J. Ulevitch,† and Dianne B. McKay* Nucleotide-binding oligomerization domain (Nod)–containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease Downloaded from model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 3 22/2 mice rapidly underwent cell death upon exposure to alloan- tigen. The Nod1 3 22/2 T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 3 22/2 T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflam- http://www.jimmunol.org/ matory states, including those associated with bone marrow or solid organ transplantation. The Journal of Immunology, 2017, 199: 000–000. he innate immune system provides rapid defense re- diseases such as inflammatory bowel disease, familial arthritis and sponses to pathogens and products of tissue injury. This uveitis syndromes, and early onset sarcoidosis (1). T primitive defense system recognizes conserved structures Nod proteins are well known to participate in the innate immune of molecules released from microbes and dead and dying cells that response against bacterial pathogens, but mounting data also bind to membrane-bound and cytosolic pattern recognition re- support a role for Nod1 and Nod2 in adaptive immune responses. by guest on October 2, 2021 ceptors (PRRs). Two well-characterized intracytosolic PRRs are The peptidoglycan products that activate Nod proteins are known the nucleotide-binding oligomerization domain (Nod)–containing adjuvants of Ag-specific Ab production (2–5). Nod2 has been proteins Nod1 and Nod2, which are members of the Nod-like shown to regulate Th17 cell responses in experimental colitis receptor family of PRRs. These proteins sense peptidoglycan models, to program human dendritic cells (DCs) to secrete IL-23, fragments of bacterial cell walls and activate intracellular sig- and to drive development of Th17 cells from memory T cells (6, naling pathways that drive proinflammatory and antimicrobial 7). Stimulation of either Nod1 or Nod2 leads to Th2-dependent responses. Over the past decade substantial data have emerged responses (8, 9) and both proteins contribute to IL-6–dependent defining key roles for Nod family members in chronic human induction of Th-17 cell responses (10). Nod1 is widely expressed in a variety of cell types, and Nod2 *Division of Nephrology and Hypertension, Department of Medicine, University of is found in hematopoietic cells and epithelial cells of the gas- California, San Diego, La Jolla, CA 92093; and †Department of Immunology and trointestinal tract and the kidney (1). Altering Nod1 and Nod2 Microbial Sciences, Scripps Research Institute, La Jolla, CA 92037 signaling has the potential to modify inflammatory disease ac- ORCIDs: 0000-0002-4748-9582 (S.G.K.); 0000-0001-7227-5757 (A.A.Shigeoka); tivity (1), and therefore it is no surprise that small molecule 0000-0001-9921-4225 (A.L.G.); 0000-0001-8293-3127 (R.J.U.); 0000-0002-4857- 6039 (D.B.M.). therapeutics are being developed to specifically target these cy- tosolic PRRs (11–13). A rational approach to modifying the Received for publication April 15, 2016. Accepted for publication May 26, 2017. activity of Nod1- and Nod2-mediated inflammation requires This work was supported by grants awarded to D.B.M. from the National Institutes of Health (R01 DK091136 and R01 DK075718) and the California Institute for Regen- an understanding of how these proteins contribute to adaptive erative Medicine (RB5-07379). immunity. To better understand how Nod1 and Nod2 proteins Address correspondence and reprint requests to Dr. Dianne B. McKay, Division contribute to T cell responses, we investigated their role in of Nephrology and Hypertension, Department of Medicine, University of alloantigen-induced T cell activation and asked whether their California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093. E-mail address: [email protected] absence impacted in vivo alloresponses using a severe acute graft The online version of this article contains supplemental material. versus host disease (GVHD) model. Abbreviations used in this article: AICD, activation-induced cell death; BM, bone marrow; CCCP, carbonyl cyanide–p-trifluoromethoxyphenylhydrazone; DC, den- Materials and Methods dritic cell; GVHD, graft versus host disease; LN, lymph node; Nod, nucleotide- Mice binding oligomerization domain; PRR, pattern recognition receptor; Treg, regulatory T cell; UCSD, University of California, San Diego; WT, wild type. All the mice used in these experiments were housed in the vivarium at University of California, San Diego (UCSD) and approved for use by the Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Institutional Animal Care and Use Committee of the UCSD Animal Re- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600667 2 LACK OF NOD1 AND NOD2 PRIMES FOR T CELL DEATH search Center. All animals were handled according to the recommendations interest: anti-cleaved caspase-8; anti-cleaved caspase-3; anti-phospho-MDM2; of the Humanities and Sciences and the Standards of the Association for anti-p53; anti BAX; or anti-b actin as a loading control (all reagents from Assessment and Accreditation of Laboratory Animal Care. BALB/c and Cell Signaling Technology, Danvers, MA). The blots were developed by C57BL/6 mice were obtained from the Jackson Laboratory, Bar Harbor ECL (Thermo Fisher Scientific, Waltham, MA). MN. The Nod12/2, Nod22/2, and Nod1 3 22/2 mice were obtained from J. Matheson at the Scripps Research Institute, La Jolla, CA. Apoptosis and mitochondrial damage Relative expression of Nod1 and Nod2 in T cells Proliferating T cells were analyzed for the cell surface expression of death markers CD95L, CD95, and TNFRa and markers of apoptosis (Annexin Vand Expression of Nod1 and Nod2 was detected in CD4+ and CD8+ T cells propidium iodide) (BioLegend) by flow cytometry. Mitochondrial damage was + + isolated from peripheral lymph nodes (LNs) of wild-type (WT) mice. To detected in CD4 and CD8 T cells by staining for mitochondrial membrane ensure the CD4+ and CD8+ T cells were not contaminated with DCs, we potential with mitoprobe JC-1 stain (Invitrogen, Carlsbad, CA) according to + labeled the cells with anti-CD11c and anti-CD11b Abs followed by pos- the manufacturer’s protocol. Briefly the CD4 and CD8+ T lymphocytes were itive selection with magnetic beads, and then negatively selected the CD4+ stimulated with CD3e+CD28 (5 mg/ml) for 24 h and then suspended in PBS 6 and CD8+ T cell population using a magnetic cell isolation and cell sep- at density of 1 3 10 cells per ml. The JC-1 dye was then added to the tubes aration column (MACS). Confirmation of T cell purity (.98%) was done to obtain a final concentration of 2 mM. For the positive control, unstimulated 6 by FACS. Expression of Nod1 and Nod2 was measured by SYBR green- cells were suspended at 1 3 10 cells per ml and carbonyl cyanide–p-tri- based real-time PCR according to the manufacturer’s recommendations fluoromethoxyphenylhydrazone (CCCP) was added to obtain a final con- (SsoAdvanced SYBR Green Supermix; Bio-Rad, Hercules, CA) with an centration of 50 mM, followed by JC-1 dye at a final concentration of 2 mM. Eco Real-Time PCR system (Illumina, San Diego, CA).
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