Human peripheral blood and bone marrow Epstein-Barr virus-specific T-cell repertoire in latent infection reveals distinct memory T-cell subsets.
EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-gamma-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-gamma alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2- and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4(+) and CD8(+) T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling early-differentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBV-associated diseases.
Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Manuel
M
Guerreiro
Il-Kang
IK
Na
Anne
A
Letsch
Doreen
D
Haase
Sandra
S
Bauer
Christian
C
Meisel
Andy
A
Roemhild
Petra
P
Reinke
Hans-Dieter
HD
Volk
Carmen
C
Scheibenbogen
D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*