Molecular basis of CD8+ T cell subset differentiation
08 / 2004 - 08 / 2009
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Viral infection induces massive expansion of antigen-specific CD8+ T cells that acquire effector functions and control spread of invading pathogens. During recovery most activated T cells die but a fraction remains and returns to a resting state. These cells provide immunological memory and importantly restrain persisting viruses. Latent viruses elicit functionally distinct CD8+ T cells. T cells specific for lymphotropic and hepatotropic viruses are mostly non-cytolytic and have the ability to produce the T cell growth factor IL-2 (memory-type). On the other side of the spectrum, CMV, a virus with a broad cellular tropism, promotes expansion of cytolytic cells that depend on exogenous growth factors for clonal expansion (effector-type). The specific contribution of these subsets in maintaining virus-host cease-fires is unknown. Moreover, the molecular mechanisms regulating CD8+ T cell differentiation have yet to be uncovered. We aim to delineate genetic programs that direct CD8+ T cell differentiation and will test if interference with particular differentiation pathways impedes establishment of viral latency. Three complementary approaches will be taken. First, DNA microarray analyses will be performed to determine gene expression profiles characteristic for the distinct differentiated CD8+ T cell subsets in mouse and human. Second, mechanisms that direct expression of CD27 and perforin, prototypic memory and effector molecules, respectively, will be studied to define lineage differentiation within the CD8+ T cell subset. Here, both transcriptional regulation and epigenetic modifications of the respective loci will be analyzed. Third, key regulators of CD8+ T cell differentiation will be used to address the importance of polarized CD8+ T cell differentiation in persistent experimental virus infections. Knowledge of the molecular details of CD8+ T cell differentiation is relevant to understand how successful immune responses have developed during evolution and will set the stage for vaccination protocols for infectious disease and immunotherapy of cancer.