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Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins.
J Virol. 2013 Dec; 87(23):12794-804.JV

Abstract

Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by neutralizing antibodies and strong T cell responses. This vaccine provides an excellent model for studying human immunity. While several studies have characterized YFV-specific antibody and CD8(+) T cell responses, less is known about YFV-specific CD4(+) T cells. Here we characterize the epitope specificity, functional attributes, and dynamics of YFV-specific T cell responses in vaccinated subjects by investigating peripheral blood mononuclear cells by using HLA-DR tetramers. A total of 112 epitopes restricted by seven common HLA-DRB1 alleles were identified. Epitopes were present within all YFV proteins, but the capsid, envelope, NS2a, and NS3 proteins had the highest epitope density. Antibody blocking demonstrated that the majority of YFV-specific T cells were HLA-DR restricted. Therefore, CD4(+) T cell responses could be effectively characterized with HLA-DR tetramers. Ex vivo tetramer analysis revealed that YFV-specific T cells persisted at frequencies ranging from 0 to 100 cells per million that are detectable years after vaccination. Longitudinal analysis indicated that YFV-specific CD4(+) T cells reached peak frequencies, often exceeding 250 cells per million, approximately 2 weeks after vaccination. As frequencies subsequently declined, YFV-specific cells regained CCR7 expression, indicating a shift from effector to central memory. Cells were typically CXCR3 positive, suggesting Th1 polarization, and produced gamma interferon and other cytokines after reactivation in vitro. Therefore, YFV elicits robust early effector CD4(+) T cell responses that contract, forming a detectable memory population.

Authors+Show Affiliations

Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24049183

Citation

James, Eddie A., et al. "Yellow Fever Vaccination Elicits Broad Functional CD4+ T Cell Responses That Recognize Structural and Nonstructural Proteins." Journal of Virology, vol. 87, no. 23, 2013, pp. 12794-804.
James EA, LaFond RE, Gates TJ, et al. Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins. J Virol. 2013;87(23):12794-804.
James, E. A., LaFond, R. E., Gates, T. J., Mai, D. T., Malhotra, U., & Kwok, W. W. (2013). Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins. Journal of Virology, 87(23), 12794-804. https://doi.org/10.1128/JVI.01160-13
James EA, et al. Yellow Fever Vaccination Elicits Broad Functional CD4+ T Cell Responses That Recognize Structural and Nonstructural Proteins. J Virol. 2013;87(23):12794-804. PubMed PMID: 24049183.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins. AU - James,Eddie A, AU - LaFond,Rebecca E, AU - Gates,Theresa J, AU - Mai,Duy T, AU - Malhotra,Uma, AU - Kwok,William W, Y1 - 2013/09/18/ PY - 2013/9/20/entrez PY - 2013/9/21/pubmed PY - 2014/1/9/medline SP - 12794 EP - 804 JF - Journal of virology JO - J Virol VL - 87 IS - 23 N2 - Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by neutralizing antibodies and strong T cell responses. This vaccine provides an excellent model for studying human immunity. While several studies have characterized YFV-specific antibody and CD8(+) T cell responses, less is known about YFV-specific CD4(+) T cells. Here we characterize the epitope specificity, functional attributes, and dynamics of YFV-specific T cell responses in vaccinated subjects by investigating peripheral blood mononuclear cells by using HLA-DR tetramers. A total of 112 epitopes restricted by seven common HLA-DRB1 alleles were identified. Epitopes were present within all YFV proteins, but the capsid, envelope, NS2a, and NS3 proteins had the highest epitope density. Antibody blocking demonstrated that the majority of YFV-specific T cells were HLA-DR restricted. Therefore, CD4(+) T cell responses could be effectively characterized with HLA-DR tetramers. Ex vivo tetramer analysis revealed that YFV-specific T cells persisted at frequencies ranging from 0 to 100 cells per million that are detectable years after vaccination. Longitudinal analysis indicated that YFV-specific CD4(+) T cells reached peak frequencies, often exceeding 250 cells per million, approximately 2 weeks after vaccination. As frequencies subsequently declined, YFV-specific cells regained CCR7 expression, indicating a shift from effector to central memory. Cells were typically CXCR3 positive, suggesting Th1 polarization, and produced gamma interferon and other cytokines after reactivation in vitro. Therefore, YFV elicits robust early effector CD4(+) T cell responses that contract, forming a detectable memory population. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/24049183/Yellow_fever_vaccination_elicits_broad_functional_CD4+_T_cell_responses_that_recognize_structural_and_nonstructural_proteins_ L2 - https://journals.asm.org/doi/10.1128/JVI.01160-13?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -