Broad influenza-specific CD8+ T-cell responses in humanized mice vaccinated with influenza virus vaccines.
The development of novel human vaccines would be greatly facilitated by the development of in vivo models that permit preclinical analysis of human immune responses. Here, we show that nonobese diabetic severe combined immunodeficiency (NOD/SCID) beta(2) microglobulin(-/-) mice, engrafted with human CD34+ hematopoietic progenitors and further reconstituted with T cells, can mount specific immune responses against influenza virus vaccines. Live attenuated trivalent influenza virus vaccine induces expansion of CD8+ T cells specific to influenza matrix protein (FluM1) and nonstructural protein 1 in blood, spleen, and lungs. On ex vivo exposure to influenza antigens, antigen-specific CD8+ T cells produce IFN-gamma and express cell-surface CD107a. FluM1-specific CD8+ T cells can be also expanded in mice vaccinated with inactivated trivalent influenza virus vaccine. Expansion of antigen-specific CD8+ T cells is dependent on reconstitution of the human myeloid compartment. Thus, this humanized mouse model permits preclinical testing of vaccines designed to induce cellular immunity, including those against influenza virus. Furthermore, this work sets the stage for systematic analysis of the in vivo functions of human DCs. This, in turn, will allow a new approach to the rational design and preclinical testing of vaccines that cannot be tested in human volunteers.
Yu
Chun I
CI
Baylor National Institute of Allergy and Infectious Diseases (NIAID) Cooperative Center for Translational Research on Human Immunology, Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
Gallegos
Michael
M
Marches
Florentina
F
Zurawski
Gerard
G
Ramilo
Octavio
O
García-Sastre
Adolfo
A
Banchereau
Jacques
J
Palucka
A Karolina
AK
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular; D007252:Influenza Vaccines / Q000276:immunology / Q000494:pharmacology*; D017710:Lymphocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000637:transplantation; D013745:Tetanus Toxoid / Q000276:immunology / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014763:Viral Matrix Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D007252:Influenza Vaccines; D013745:Tetanus Toxoid; D014763:Viral Matrix Proteins; D017361:Viral Nonstructural Proteins; D001613:beta 2-Microglobulin