Terminal deoxynucleotidyl transferase establishes and broadens antiviral CD8+ T cell immunodominance hierarchies.
The action of TdT on mouse TCR genes accounts for approximately 90% of T cell repertoire diversity. We report that in TdT-/- mice, total T(CD8+) responses to influenza and vaccinia viruses are reduced by approximately 30% relative to wild-type mice. We find that T(CD8+) responses to three subdominant influenza virus determinants are reduced to background values in TdT-/- mice while responses to three immunodominant determinants undergo a major reshuffling. A similar reshuffling occurs in T(CD8+) responses to immunodominant vaccinia virus determinants, and is clearly based on broad differences in TCR family usage and CDR3 length between wild-type and TdT-/- mice. These findings demonstrate that TdT plays a critical role in the magnitude and breadth of anti-viral T(CD8+) responses toward individual determinants and suggests that germline TCR repertoire bias toward the most dominant determinants is a major factor in establishing immunodominance hierarchies.
Haeryfar
S M Mansour
SM
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mansour.haeryfar@schulich.uwo.ca
Hickman
Heather D
HD
Irvine
Kari R
KR
Tscharke
David C
DC
Bennink
Jack R
JR
Yewdell
Jonathan W
JW
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D004253:DNA Nucleotidylexotransferase / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D009980:Influenza A virus / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology
D000956:Antigens, Viral; D011948:Receptors, Antigen, T-Cell; D004253:DNA Nucleotidylexotransferase