DNA methylation by DNA methyltransferase 1 is critical for effector CD8 T cell expansion.
Transcriptional silencing mediated by DNA methylation is a critical component of epigenetic regulation during early embryonic development in animals. However, the requirement for DNA methylation during activation and differentiation of mature CD8+ T cells into effector and memory cells is not clear. Using cre-mediated deletion of DNA methyltransferase 1 (Dnmt1) at the time of CD8+ T cell activation, we investigated the obligation for maintaining patterns of DNA methylation during the generation of Ag-specific effector and memory CD8+ T cells in response to acute viral infection of mice with lymphocytic choriomeningitis virus. Dnmt1-/- CD8+ T cells failed to undergo the massive CD8+ T cell expansion characteristic of lymphocytic choriomeningitis virus infection, leading to >80% reductions in Ag-specific effector CD8+ T cells at the height of the response. Despite this, Dnmt1-/- CD8+ T cells efficiently controlled the viral infection. Interestingly, the number of Ag-specific Dnmt1-/- memory CD8+ T cells was moderately reduced compared with the reductions seen at day 8 postinfection. Our data suggest that ablation of Dnmt1 and subsequent DNA methylation affect the finite proliferative potential of Ag-specific CD8+ T cells with moderate effects on their differentiation to effector and memory CD8+ T cells.
Emory Vaccine Center, Department of Microbiology and Immunology, Emory University, Atlanta, GA 30329, USA.
Craig
C
Chappell
Caroline
C
Beard
John
J
Altman
Rudolph
R
Jaenisch
Joshy
J
Jacob
D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D007156:Immunologic Memory; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D000956:Antigens, Viral; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse