OHSU

Nolz Lab Research Interests

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

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Figure 1:  Molecular interactions dictating trafficking of T cells into (A) lymph nodes through high endothelial venules or (B) inflamed tissues through vascular endothelium.
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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 b1-6 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.
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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.