The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response.
The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.
Akondy
Rama S
RS
Emory Vaccine Center and the Hope Clinic, Emory University School of Medicine, Atlanta, GA 30022, USA.
Monson
Nathan D
ND
Miller
Joseph D
JD
Edupuganti
Srilatha
S
Teuwen
Dirk
D
Wu
Hong
H
Quyyumi
Farah
F
Garg
Seema
S
Altman
John D
JD
Del Rio
Carlos
C
Keyserling
Harry L
HL
Ploss
Alexander
A
Rice
Charles M
CM
Orenstein
Walter A
WA
Mulligan
Mark J
MJ
Ahmed
Rafi
R
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000940:Antigenic Variation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D045142:Cross-Priming / Q000276:immunology; D003430:Cross-Sectional Studies; D015789:HLA-A2 Antigen / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D007156:Immunologic Memory; D008137:Longitudinal Studies; D008969:Molecular Sequence Data; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000008:administration & dosage / Q000276:immunology; D015004:Yellow Fever / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D022341:Yellow Fever Vaccine / Q000008:administration & dosage / Q000276:immunology*; D015005:Yellow fever virus / Q000276:immunology*; D055815:Young Adult
D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; C080107:NS4B protein, flavivirus; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit; D017361:Viral Nonstructural Proteins; D022341:Yellow Fever Vaccine