Antigen-experienced memory T cells constitute a diverse, heterogeneous population of immune cells that is generated throughout life in response to a variety of pathogens, vaccines, allergens, self-antigens and other environment factors. In fact, as we age, generation of new nave T cells diminishes and memory T cell populations dominate the repertoire. Thus, the basic mechanisms that regulate the functions of diverse memory T cell populations has broad relevance for a variety of diseases and pathological conditions including vaccine designs, immunotherapy protocols and treatment or prevention of inflammatory or autoimmune disorders. Although the formation and differentiation of memory CD8+ and CD4+ T cells in the circulation has been extensively characterized, the capacity for memory T cells to actively home to and infiltrate tissues where they exhibit their effector functions is less understood. We have recently discovered that memory CD8+ T cells require post-translational O-linked glycosylation of selectin ligands for trafficking to and infiltrating non- lymphoid tissues. Furthermore, we identified that de novo synthesis of core 2 O-glycans is restricted to memory T cells and can be regulated in an antigen-independent manner. However, the basic molecular mechanisms regulating core 2 O-glycan synthesis and trafficking of memory CD8+ and CD4+ T cells during infections are yet to be fully characterized. Specifically, we will 1) determine if different CD8+ T cell populations have the capacity to synthesize core 2 O-glycans and traffic into non-lymphoid tissues, 2) define the molecular and transcriptional mechanisms that regulate core 2 O-glycan synthesis in memory CD8+ T cells, and 3) determine if memory CD4+ T cells require core 2 O-glycan synthesis to traffic into non-lymphoid tissues during either acute or chronic viral infections. Thus, the overall goal of our study will be to identify and characterize the mechanisms regulating the trafficking of diverse memory T cell populations and how this can be enhanced (for host protection) or inhibited (for allergies or autoimmunity).
Antigen-specific memory T cells can protect against infections, but also contribute to inflammatory and autoimmune disorders. We have recently found that cell intrinsic changes in post-translational glycosylation of surface proteins regulate the capacity for memory T cells to leave the circulation and traffic into non-lymphoid tissues where they exhibit their effector functions. Therefore, the goals of this proposal will be to determine how diverse populations of memory CD8+ and CD4+ T cells regulate O-glycan synthesis and traffic into non- lymphoid tissues, which will contribute to the long-term goal of improving vaccine design and immunotherapy techniques.
| 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 |
| 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: |
