Clonal dynamics of memory CD8 T cell inflation
Full title: Clonal dynamics of memory CD8 T cell inflation
Grantors: Swiss - Croatian Cooperation Programme
Grantor’s website: https://www.swiss-cro.hr
Grant number: 180552
Duration: 01.02.2019 - 31.01.2022
Coordinator: Annette Oxenius, Prof. Dr., Institute of Microbiology, ETH Zurich and Astrid Krmpotić, Prof. Dr., University of Rijeka, Faculty of Medicine
Total funding: CHF 399.583,00
Total funding (MEDRI): CHF 199.050,00
A hallmark of immunological memory is the ability of the adaptive immune system to generate long-lived antigen-specific memory T or B cells that provide rapid protection upon a secondary infection with a similar pathogen. This is the basis for vaccination. The induction of memory T cells that reside in peripheral tissues, instead of the lymphoid tissue, is of considerable interest for T cell based vaccines so that in case of pathogen encounter at mucosal and barrier sites, they can immediately exert their effector functions and rapidly control the infection. On the other hand, memory CD8 T cells, which reside in the lymph nodes are required to provide an optimal response to the pathogen challenge as they serve as a source of secondary effector CD8 T cells. Cytomegalovirus (CMV)-based vaccines support the induction and accumulation of large amounts of effector memory CD8 T cells in peripheral tissues, a process called memory inflation. In many tissues, these inflationary T cells are connected to the circulation and need to be continuously replenished for their maintenance at high numbers. The parameters that control the inflationary T cell pool are only beginning to be understood. One key prerequisite is the presentation of antigen in latently infected non-hematopoietic cells, however the exact cellular source is currently unknown.
Our current hypothesis is that proliferation-competent inflationary T cells, which are predominantly found in lymph nodes, are reactivated in the lymph node when they are exposed to viral antigen presented on latently infected non-hematopoietic cells in this tissue. In this proposal, we will build on this theory and delineate in the experimental model of mouse CMV (MCMV) infection the costimulatory requirement that foster expansion of CMV-specific CD8 T cells during viral latency and the spatio-temporal clonal composition of inflationary CD8 T cells. Using individual genetically traceable MCMV-specific CD8 T cells in adoptive transfer experiments will allow us to decompose the clonal composition and relationship of inflationary CD8 T cells over time and across tissues. If our hypothesis is correct, then we should measure a higher clonal diversity in lymph nodes (LNs) and a more restricted diversity in the peripherally inflated pool of MCMV-specific T cells. The use of genetically modified viruses that direct altered expression of costimulatory molecules in infected cells will provide important information about the relevance of co-stimulation for the extent of memory CD8 T cell inflation as well as its impact on the clonal composition of the inflated memory CD8 T cell pool. In addition to the establishment of the genealogy of inflating MCMV-specific CD8 T cells, we will also evaluate, on a functional level, the longitudinal evolution of avidities of the inflating populations of CD8 T cells.
The success of CMV-based vaccines is due to the induction of the large population of functional inflationary T cells, therefore, understanding how this effector memory pool is generated and maintained is pivotal for exploiting CMV-based vaccines.