EBV promotes human CD8 NKT cell development.
The reports on the origin of human CD8(+) Valpha24(+) T-cell receptor (TCR) natural killer T (NKT) cells are controversial. The underlying mechanism that controls human CD4 versus CD8 NKT cell development is not well-characterized. In the present study, we have studied total 177 eligible patients and subjects including 128 healthy latent Epstein-Barr-virus(EBV)-infected subjects, 17 newly-onset acute infectious mononucleosis patients, 16 newly-diagnosed EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. We have established human-thymus/liver-SCID chimera, reaggregated thymic organ culture, and fetal thymic organ culture. We here show that the average frequency of total and CD8(+) NKT cells in PBMCs from 128 healthy latent EBV-infected subjects is significantly higher than in 17 acute EBV infectious mononucleosis patients, 16 EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. However, the frequency of total and CD8(+) NKT cells is remarkably increased in the acute EBV infectious mononucleosis patients at year 1 post-onset. EBV-challenge promotes CD8(+) NKT cell development in the thymus of human-thymus/liver-SCID chimeras. The frequency of total (3% of thymic cells) and CD8(+) NKT cells ( approximately 25% of NKT cells) is significantly increased in EBV-challenged chimeras, compared to those in the unchallenged chimeras (<0.01% of thymic cells, CD8(+) NKT cells undetectable, respectively). The EBV-induced increase in thymic NKT cells is also reflected in the periphery, where there is an increase in total and CD8(+) NKT cells in liver and peripheral blood in EBV-challenged chimeras. EBV-induced thymic CD8(+) NKT cells display an activated memory phenotype (CD69(+)CD45RO(hi)CD161(+)CD62L(lo)). After EBV-challenge, a proportion of NKT precursors diverges from DP thymocytes, develops and differentiates into mature CD8(+) NKT cells in thymus in EBV-challenged human-thymus/liver-SCID chimeras or reaggregated thymic organ cultures. Thymic antigen-presenting EBV-infected dendritic cells are required for this process. IL-7, produced mainly by thymic dendritic cells, is a major and essential factor for CD8(+) NKT cell differentiation in EBV-challenged human-thymus/liver-SCID chimeras and fetal thymic organ cultures. Additionally, these EBV-induced CD8(+) NKT cells produce remarkably more perforin than that in counterpart CD4(+) NKT cells, and predominately express CD8alphaalpha homodimer in their co-receptor. Thus, upon interaction with certain viruses, CD8 lineage-specific NKT cells are developed, differentiated and matured intrathymically, a finding with potential therapeutic importance against viral infections and tumors.
He
Yuling
Y
Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China. flying_bird2004@sina.com
Xiao
Ruijing
R
Ji
Xiang
X
Li
Li
L
Chen
Lang
L
Xiong
Jie
J
Xiao
Wei
W
Wang
Yujuan
Y
Zhang
Lijun
L
Zhou
Rui
R
Tan
Xinti
X
Bi
Yongyi
Y
Jiang
Yan-Ping
YP
Jin
Youxin
Y
Tan
Jinquan
J
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D002678:Chimera; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology; D006801:Humans; D007244:Infectious Mononucleosis / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D009924:Organ Culture Techniques; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000821:virology
C508605:IL7 protein, human; D015851:Interleukin-7; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma