OHSU

Jeffrey C. Nolz, PhD

jeffery-nolzTitle:

Assistant Professor

Department:

Radiation Medicine

Specialty:

Microbiology

Education:

Ph.D. Biomedical Sciences (immunology), Mayo Clinic College of Medicine, November 2007
B.S. Biological Sciences (highest Honors), South Dakota State University, May 2003

Courses:

AAI Advanced Course in Immunology, August 2004

university Service:

Chapter Adviser, Sigma Phi Epsilon Fraternity, Iowa Gamma Chapter, University of Iowa, (2008-Present)
Sigma Phi Epsilon, Volunteer of the Year-District 17 (2011)

Collaborative Recruitment Pool:

The Scientific Advisory Board for the School of Medicine’s Collaborative Recruitment Pool Approval

Professional Experience:

  • (2008-Present) Postdoctoral Research Fellow, Laboratory of John T. Harty, Department of Microbiology, University of Iowa 
  • (2003-2007) Graduate Student, Laboratory of Daniel D. Billadeau, Department of Immunology, Mayo Clinic College of Medicine. Thesis: “Characterizing the Multiple Functions of the WAVE2 Complex During T Cell Activation”
  • (2002-2003) Undergraduate Research Assistant, Laboratory of Ronald Utecht, Department of Chemistry, South Dakota State University
  • (2002) Research Experience for Undergraduates, Sponsored by the National Science Foundation, Department of Biochemistry, University of South Dakota, Laboratory of Gary D. Small Project: “The Role of Phosphorylation in Light-Induced Degradation of CPH Proteins in Chlamydomonas”
  • (2000-2001) Teaching Assistant South Dakota State University, Department of Biology/Microbiology, Instructed Labs for Zool 221 (Human Anatomy)

Professional Society Memberships:

(2012-Present)  The American Association of Immunologists

Award and Honors:

  • (2007-2008) Appointee, NIH T32-AI07425 Training Grant—Immunology, Mayo Clinic College of Medicine
  • (2008-2009) Appointee, NIH T32-AI07343 Training Grant—Infectious Diseases, University of Iowa
  • (2009-2012) Career Development Award (Fellow), ($165,000, Salary Support Only), Leukemia and Lymphoma Society
  • (2010) Future of Science Fund Scholarship, Keystone Symposia, Viral Immunity
  • (2011) Future of Science Fund Scholarship, Keystone Symposia, New Frontiers at the Interface of Immunity and Glycobiology
  • (2012-Present) Appointee, NIH T32-AI07260 Training Grant—Immunology, University of Iowa
  • (2013) AAI Trainee Abstract Travel Award

Community Outreach Presentations:

Leukemia and Lymphoma Society, Iowa Chapter, ‘Booster Immunizations: Strategies and Implications’, March 2012

Lab Description:

Trafficking of T cells out of the circulation and into various tissues is a highly orchestrated process involving multiple receptor – ligand interactions. In my laboratory, we utilize a wide variety of disease models combined with molecular and cellular approaches aimed at ultimately understanding the biochemical signals that dictate T cell localization in vivo.

The selectin family of proteins (L-, P-, and E-selectin) play a critical role in regulating immune cell trafficking and facilitate the initial interactions between T cells and vascular endothelium prior to chemokine-mediated signaling and integrin activation (Figure 1). Importantly, ligands for selectins require post-translational glycosylation (Figure 2) to become functional and both CD8+ and CD4+ T cells exhibit dynamic regulation of the enzymes that are responsible for generating these O-linked glycan structures. Furthermore, we have recently discovered that the generation of core 2 O-glycans within memory CD8+ T cell populations occurs in an antigen-independent manner, but rather is controlled by inflammatory cytokines (Figure 3). In addition, we have shown that this is a major regulatory mechanism controlling memory CD8+ T cell recruitment to inflamed tissue prior to antigen re-encounter. Thus, a comprehensive understanding of the molecular and biological mechanisms that regulate T cell O-glycan synthesis and trafficking could ultimately result in new disease prevention strategies by therapeutically directing (for vaccines and tumor immunotherapy) or inhibiting (for autoimmunity) T cell recruitment to target tissues.

Current projects in the laboratory include:
1) Mechanisms of CD8+ and CD4+ T cell recruitment to inflamed tissues and tumors
2) Molecular and biochemical regulation of core 2 O-glycan synthesis in memory CD8+ T cell populations
3) Regulation of core 2 O-glycan synthesis and T cell trafficking during chronic infections
4) T cell-mediated immunity against viral infection of peripheral tissues
5) T cell-mediated tumor immunotherapy

Figure 1: Molecular interactions dictating trafficking of T cells into (A) lymph nodes through high endothelial venules or (B) inflamed tissues through vascular endothelium.

Figure 2: The core 1 O-glycan structure originating from a serine or threonine amino acid (S/T) is formed by the addition of galactose in a β1-3 linkage to N-acetylgalactosamine. Generation of the core 2 structure occurs following activity of Gcnt1, which catalyzes the addition of N-acetylglucosamine in a 1-6 linkage on the core 1 structure. Subsequent action by other glycotransferases ultimately results in core 2 O-glycan extension and generation of the sialyl Lewis X, which mediates selectin – selectin ligand interactions.

Figure 3: Naive CD8+ T cells express core 1 O-glycans, but not core 2 O-glycans and cannot bind to P- or E-selectin. Following antigen encounter, CD8+ T cells rapidly express extended core 2 O-glycans, bind to P- and E-selectin, and undergo chromatin remodeling at the Gcnt1 gene locus. Over time, most memory CD8+ T cells lose expression of core 2 O-glycans and cannot bind to P- or E-selectin during the steady state (non-inflamed) environment. However, the Gcnt1 gene locus remains in an open chromatin configuration and, following exposure to IL-15 during an inflammatory challenge, will rapidly generate core 2 O-glycans, bind to both P- and E-selectin, and efficiently localize to inflamed tissue.

Publications:

Nolz JC, Harty JT
Inflammatory IL-15 regulates memory CD8+ T cell O-glycan synthesis and trafficking .
Under Revision, Journal of Clinical Investigation

Nolz JC, Harty JT
One bug or another: promiscuous T cells form lifelong memory.
Immunity. 2013. Feb 21;38(2):207-8. Preview.

Richer MJ, Nolz JC, Harty JT.
Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8+ T cells by enhancing T cell receptor signaling.
Immunity. 2013 Jan 24;38(1):140-52

Nolz JC, Rai D, Badovinac VP, Harty JT.
Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells.
Proc Natl Acad Sci U S A. 2012 Apr;109(16):6199-204

Nolz JC, Starbeck-Miller GR, Harty JT.
Naïve, effector, and memory CD8 T cell trafficking: parallels and distinctions.
Immunotherapy. 2011 Oct;3(10):1223-33. Review.

Nolz JC, Harty JT.
Strategies and implications for prime-boost vaccination to generate memory CD8 T cells.
Adv Exp Med Biol. 2011;780:69-83. Review.

Butler NS*, Nolz JC*, Harty JT
*These Authors Contributed Equally
Immunologic considerations for generating memory CD8 T cells through vaccination.
Cell Microbiol. 2011 Jul;13(7):925-33. Review.

Nolz JC, Harty JT.
Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection.
Immunity. 2011 May 27;34(5):781-93.

Nolz JC, Nacusi LP, Segovis CM, Medeiros RB, Mitchell JS, Shimizu Y, Billadeau DD.
The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1.
J Cell Biol. 2008 Sep 22;182(6):1231-44.

Nolz JC, Medeiros RB, Mitchell JS, Zhu P, Freedman BD, Shimizu Y, Billadeau DD.
WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse.
Mol Cell Biol. 2007 Sep;27(17):5986-6000.

Nolz JC, Fernandez-Zapico ME, Billadeau DD.
TCR/CD28-stimulated actin dynamics are required for NFAT1-mediated transcription of c-rel leading to CD28 response element activation.
J Immunol. 2007 Jul 15;179(2):1104-12.

Billadeau DD, Nolz JC, Gomez TS.
Regulation of T-cell activation by the cytoskeleton.
Nat Rev Immunol. 2007 Feb;7(2):131-43. Review.

Gomez TS, McCarney SD, Carrizosa E, Labno CM, Comiskey EO, Nolz JC, Zhu P, Freedman BD, Clark MR, Rawlings DJ, Billadeau DD, Burkhardt JK.
HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse.
Immunity. 2006 Jun;24(6):741-52.

Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, Shimizu Y, Burkhardt JK, Freedman BD, Billadeau DD.
The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation.
Curr Biol. 2006 Jan 10;16(1):24-34.

Nolz JC, Gomez TS, Billadeau DD.
The Ezh2 methyltransferase complex: actin up in the cytosol.
Trends Cell Biol. 2005 Oct;15(10):514-7.

Nolz JC, Tschumper RC, Pittner BT, Darce JR, Kay NE, Jelinek DF.
ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype.
Leukemia. 2005 Jun;19(6):1018-24.

Support:

1K22AI102981-01A1 NIH/NIAID--$250,000 Direct Costs
Regulation of Memory CD8 T cell Trafficking to Inflamed Tissues
Priority Score = 20. (Fundable Priority Score, Notification of Successful Phase I Completion)

Oral Presentations and Scientific Meetings:

96th Annual Meeting of The American Association of Immunologists (May 2009), Nolz JC and Harty JT.
‘Multiple Antigen Encounters Decrease Memory CD8 T Cell-Mediated Protection Against Chronic Viral Infection’ [Poster/Invited Oral Presenter]

Keystone Symposia—Viral Immunity (March 2010), Nolz JC and Harty JT.
‘Multiple Antigen Encounters Decrease the Protective Capacity of the Ensuing Memory CD8 T Cell Population Against Chronic LCMV Infection’ [Poster/Invited Oral Presenter]

Keystone Symposia—New Frontiers at the Interface of Immunity and Glycobiology (March 2011), Nolz JC and Harty JT.
‘Inflammation is Sufficient to Drive Selectin Ligand Expression on Memory CD8 T cells Resulting in Trafficking to Inflamed Tissues’ [Poster/Invited Oral Presenter]

Keystone Symposia—Chemokines and Leukocyte Trafficking in Homeostasis and Inflammation (January 2012), Nolz JC and Harty JT.
‘Dynamic Expression of Selectin Ligands Directs Memory CD8 T cells to Inflamed Tissues Independent of Antigenic Stimulation’ [Poster/Invited Oral Presenter]

100th Annual Meeting of the American Association of Immunologists (May 2013), Nolz JC and Harty JT.
‘Memory CD8 T cells are Programmed to Rapidly Synthesis Core 2 O-glycans for Tissue Specific Trafficking in Response to Inflammatory Cues’ [Poster/Invited Oral Presenter]

Poster Presentations at Scientific Meetings:

National Conference for Undergraduate Research (April 2003)
Nolz JC and Small GD. ‘The Role of Phosphorylation in Light-Induced Degradation of CPH Proteins in Chlamydomonas’

Keystone Symposia—Lymphocyte Activation and Signaling (Jan 2006)
Nolz JC, Gomez TS, Zhu P, Shuixing L, Medeiros RB, Shimizu Y, Burkhardt JK, Freedman BD, Billadeau DD. ‘WAVE2 Regulates Actin Cytoskeletal Reorganization and CRAC-Mediated Calcium Entry During T Cell Activation’

Autumn Immunology Conference (Nov 2006)
Nolz JC, Medeiros RB, Zhu P, Freedman BD, Shimizu Y, Billadeau DD.
‘WAVE2 Controls TCR-Mediated Integrin Activation Through an Association with ARP2/3 and Vinculin’

Autumn Immunology Conference (Nov 2007)
Nolz JC, Nacusi LP, Medeiros RB, Mitchell JS, Shimizu Y, Billadeau DD.
‘Abl Tyrosine Kinase Associates with the WAVE2 Complex to Regulate CrkL/C3G-Mediated Activation of Rap1’