Genetics of CD8 T cell memory
Immunological memory provides improved long-term protection against re-infection by previously encountered pathogens. Upon acute viral infection, pathogen-specific T lymphocytes multiply rapidly and acquire effector functions that enable them to kill infected cells. This expansion phase is followed by a period of massive cell death (contraction) which eliminates more than 90% of antigen-specific T cells. The remaining 10% constitute the pool of long-term memory T lymphocytes. To become antigen-specific memory, T cells have therefore not only to escape cell death but also enter a state of quiescence to avoid replicative senescence. Despite the considerable incidence of viral infections affecting mankind worldwide and the crucial role played by memory CD8 T cells in the antiviral immune response, only a handful of genes have been shown in vivo to control the development and maintenance of memory T cells.
To identify new genes required for the development and maintenance of memory T cells, we are using an in vivo forward genetic strategy. This unbiased approach is, to date, the only way to identify new genes and new genes' function in a phenomenon of interest. We have created ethyl-n-nitrosourea (ENU) germline mutant lines which have been individually screened for their CD8 T cell immune response to virus in an in vivo model of infection. Three mutations affecting the development, contraction and long-term maintenance of anti-viral CD8 T cells have been isolated and positionaly cloned. The effect of the mutations on CD8 T cells' immune response and the immune system in general is currently being characterised.
Forward genetic analysis of CD8+ T cell memory, Immunology in Medicine Seminar Cambridge, University of Cambridge, 2013