Following infection or successful vaccination, nave CD8 T cells undergo a programmed series of biological events that ultimately results in the formation of a long-lived memory population. Besides the overall quantitative increase in antigen-specific CD8 T cells that occurs following vaccination, several qualitative differences have also been described that enhance the ability for memory CD8 T cells to protect against re-infection. Specifically, memory CD8 T cells are able to localize to peripheral tissues, express mediators of cytolysis including perforin and granzymes, and immediately produce cytokines following antigen recognition. In addition, recent experimental evidence has demonstrated that memory CD8 T cells are rapidly recruited to inflamed tissues following infection in an antigen-independent manner. Furthermore, these newly recruited cells are highly cytolytic and are critical mediators of protective immunity against pathogens expressing cognate antigen. Although antigen-independent recruitment of memory CD8 T cells to the lung airways has been shown to be dependent upon the CCR5 chemokine receptor, additional molecular mechanisms and biological processes that control the recruitment of memory CD8 T cells to inflamed tissues remain unknown. A complete understanding of the mechanisms controlling memory CD8 T cell localization could potentially lead to new disease prevention strategies by either directing (for pathogens and tumors) or inhibiting (for allergies and autoimmunity) localization of these cells to specific anatomical locations. Thus, the goal of this project is to determine the molecular mechanisms that control memory CD8 T cell recruitment to inflamed tissues. As detailed in the preliminary data section of this proposal, we show that following an inflammatory challenge, memory CD8 T cells exhibit the unique ability to rapidly and specifically express cell surface O-glycans, independent of antigen recognition, that results in the formation of functional ligands fo both P- and E-Selectin. In vitro studies of CD8 T cell activation have suggested that at least two glycotransferases can become expressed that are thought to be critical for the formation of O-glycans on selectin ligands, core 2 1-6-N- glucosaminyltransferase-I (Gcnt1) and ?-(1,3)-fucosyltransferase-VII (Fut7). However, the regulation of these glycotransferases in memory CD8 T cells is currently unknown. Therefore, the experiments outlined in this proposal will test the central hypothesis that inflammation drives expression of Gcnt1 and Fut7 in memory CD8 T cells, resulting in the formation of P- and E-selectin ligands and localization to inflamed tissue. Specifically, we will determine 1) whether the promoter regions of the Gcnt1 and Fut7 genes have undergone specific epigenetic changes that allow them to be rapidly expressed, 2) whether IL-15-mediated signaling in memory CD8 T cells drives selectin ligand expression, and 3) if PSGL-1 regulates recruitment of memory CD8 T cells to inflamed tissues.
Following infection or vaccination, pathogen-specific memory T cells are stably maintained for long periods of time and can effectively protect against re-infection. Interestingly, recent data have demonstrated that memory T cells rapidly localize to areas of inflammation during infections or re-infections, thus identifying a key qualitative difference between memory and nave T cells. The immediate goal of this proposal is to understand the molecular mechanisms that control memory CD8 T cell trafficking to inflamed tissues, which will contribute to the long-term goal of improving vaccine and immunotherapy design.
| Hobbs, Samuel J; Osborn, Jossef F; Nolz, Jeffrey C (2018) Activation and trafficking of CD8+ T cells during viral skin infection: immunological lessons learned from vaccinia virus. Curr Opin Virol 28:12-19 |
| Hobbs, Samuel J; Nolz, Jeffrey C (2017) Regulation of T Cell Trafficking by Enzymatic Synthesis of O-Glycans. Front Immunol 8:600 |
| Osborn, Jossef F; Mooster, Jana L; Hobbs, Samuel J et al. (2017) Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8+ T cells. Sci Immunol 2: |
| Khan, Tahsin N; Mooster, Jana L; Kilgore, Augustus M et al. (2016) Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J Exp Med 213:951-66 |
| Nolz, Jeffrey C (2015) Molecular mechanisms of CD8(+) T cell trafficking and localization. Cell Mol Life Sci 72:2461-73 |
| Nolz, Jeffrey C; Harty, John T (2014) IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Invest 124:1013-26 |
