Genetics of memory T cells
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.
Enquiries with CV welcome
et al., 2018, C1q restrains autoimmunity and viral infection by regulating CD8(+) T cell metabolism, Science, Vol:360, ISSN:0036-8075, Pages:558-563
et al., 2015, The protein LEM promotes CD8(+) T cell immunity through effects on mitochondrial respiration, Science, Vol:348, ISSN:0036-8075, Pages:995-1001
et al., 2014, N-Ethyl-N-nitrosourea mutagenesis in the mouse provides strong genetic and in vivo evidence for the role of the Caspase Recruitment Domain (CARD) of CARD-MAGUK1 in T regulatory cell development, Immunology, Vol:141, ISSN:0019-2805, Pages:446-456
et al., 2012, Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease., Proc Natl Acad Sci U S A, Vol:109, Pages:13733-13738
et al., 2012, A Deficiency in Nucleoside Salvage Impairs Murine Lymphocyte Development, Homeostasis, and Survival, Journal of Immunology, Vol:188, ISSN:0022-1767, Pages:3920-3927