Mechanisms of maintenance CD8+ T cell memory responses (Memory Inflation) upon vaccination
Final Report Abstract
During my research time in the laboratory of Professor Paul Klenerman, I have been working on T cell immunology of CD8+ T cells using a murine model of cytomegalovirus infection (MCMV) and adenovirus infection. Next to the characterization of phenotypic and functional properties of antigen-specific CD8+ T cells in these models, we also examined transcriptional profiles in antigen-specific cells localized in distinct compartments on a single-cell level: (i) a classical TCM compartment like the spleen and (ii) a TEM/TRM compartment: intestinal tissue. We identified characteristic differences in intestinal antigen-specific cells in both MCMV infection and upon vaccination with an adenoviral vector, in comparison to splenic antigen-specific cells, including upregulation of tissue-residency markers and chemokine receptors such as CX3CR1. With CMV colitis constituting a relevant disease entity in immunodeficient patients, we will further investigate the role CMV in Inflammatory Bowel Disease, such as Ulcerative Colitis. Next to a phenotypic characterization of inflationary T cells in distinct compartments, we furthermore examined metabolic traits of antigen-specific, inflationary and conventional CD8+ T cells, which are generally metabolically active and show enhanced lipid metabolism. This has also been confirmed in human long-lived CMV-specific CD8+ T cells. Finally, we investigated the metabolism of mucosal-associated invariant T (MAIT) cells ex vivo in a cohort of healthy donors. The main finding of this study was that MAIT cells are metabolically quiescent and upregulate granzyme B upon stimulation, which was dependent on a functioning glycolytic pathway. Further definition of their metabolic traits in vivo, especially under conditions of inflammation and hypoxia is of future interest, which could, by the modulation of their functions, open new therapeutic options.
Publications
- Human MAIT cells show metabolic quiescence with rapid glucose-dependent upregulation of granzyme B upon stimulation. Immunol Cell Biol. 2018
Zinser ME, Highton AJ, Kurioka A, Kronsteiner B, Hagel J, … Klenerman P.
(See online at https://doi.org/10.1111/imcb.12020) - Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8(+) T Cells by Persistent Viruses and Vaccines. Cell Rep 2018;23:768–82
Gordon CL, Lee LN, Swadling L, Hutchings C, Zinser M, … Klenerman P.
(See online at https://dx.doi.org/10.2139/ssrn.3151996)
