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
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.